TWI781117B - Cereblon-based heterodimerizable chimeric antigen receptors - Google Patents

Cereblon-based heterodimerizable chimeric antigen receptors Download PDF

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TWI781117B
TWI781117B TW106136204A TW106136204A TWI781117B TW I781117 B TWI781117 B TW I781117B TW 106136204 A TW106136204 A TW 106136204A TW 106136204 A TW106136204 A TW 106136204A TW I781117 B TWI781117 B TW I781117B
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水蟾 徐
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美商西建公司
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Abstract

Provided herein are modified T lymphocytes comprising chimeric receptors and methods of use thereof.

Description

基於CEREBLON之異二聚化之嵌合抗原受體CEREBLON-Based Heterodimerization of Chimeric Antigen Receptors

本文中之揭示內容係關於免疫學領域，且更特定言之，係關於T淋巴球或其他免疫細胞之修飾。The disclosure herein relates to the field of immunology, and more particularly, to the modification of T lymphocytes or other immune cells.

免疫系統之細胞(諸如，T淋巴球(亦被稱作T細胞))經由受體或受體複合體識別特異性抗原且與該特異性抗原相互作用，在識別此類抗原或與此類抗原相互作用之後受體或受體複合體引起細胞之活化。此受體之一實例為抗原特異性T淋巴球受體複合體(TCR/CD3) (八個蛋白之複合體)。T細胞受體(TCR)在T淋巴球之表面上表現。具有恆定結構之一種組分(CD3)對在TCR由配位體佔用之後的胞內信號傳導負責。用於抗原CD3複合體(TCR/CD3)之T淋巴球受體識別藉由主要組織相容複合體(MHC)之蛋白呈現於其的抗原肽。MHC及肽之複合體在抗原呈現細胞及其他T淋巴球靶標之表面上表現。刺激TCR/CD3複合體導致T淋巴球之活化及隨之而來的抗原特異性免疫反應。TCR/CD3複合體在免疫系統之效應功能及調節中發揮主要作用。 T淋巴球需要第二共刺激信號變得完全有效。在無此信號之情況下，T淋巴球不回應於與TCR結合之抗原，或變得無變應性。舉例而言，此共刺激信號由與抗原產生細胞上之CD80及CD86相互作用的CD28 (T淋巴球蛋白)提供。ICOS (誘導型共刺激) (另一T淋巴球蛋白)在與ICOS配位體結合時提供共刺激信號。 嵌合抗原受體(CAR)為經基因工程改造以含有TCR複合體之必需抗原結合、信號傳導及刺激功能之多肽。攜帶此類CAR之T淋巴球大體被稱為CAR-T細胞或CAR-T淋巴球。然而，雖然CAR可有效地將T淋巴球靶向特異性腫瘤相關或腫瘤特異性抗原，但亦可靶向亦表現此類抗原之正常、健康細胞。本文描述克服當前CAR設計之此缺點之經修飾嵌合受體。Cells of the immune system, such as T lymphocytes (also known as T cells), recognize and interact with specific antigens via receptors or receptor complexes, upon recognition of such antigens or with such antigens The receptor or receptor complex following the interaction causes activation of the cell. An example of such a receptor is the antigen-specific T lymphocyte receptor complex (TCR/CD3) (a complex of eight proteins). The T cell receptor (TCR) is expressed on the surface of T lymphocytes. One component (CD3) with a constant structure is responsible for intracellular signaling after TCR occupancy by ligand. The T-lymphocyte receptor for the antigen-CD3 complex (TCR/CD3) recognizes antigenic peptides presented to it by proteins of the major histocompatibility complex (MHC). Complexes of MHC and peptides are expressed on the surface of antigen presenting cells and other T lymphocyte targets. Stimulation of the TCR/CD3 complex results in the activation of T lymphocytes and the ensuing antigen-specific immune response. The TCR/CD3 complex plays a major role in the effector functions and regulation of the immune system. T lymphocytes require a second co-stimulatory signal to become fully effective. In the absence of this signal, T lymphocytes do not respond to antigens bound to the TCR, or become anergic. For example, this co-stimulatory signal is provided by CD28 (T lymphoglobulin) interacting with CD80 and CD86 on antigen producing cells. ICOS (Inducible Costimulation), another T lymphoglobulin, provides a costimulatory signal when bound to an ICOS ligand. Chimeric antigen receptors (CARs) are polypeptides that have been genetically engineered to contain the essential antigen binding, signaling and stimulatory functions of the TCR complex. T lymphocytes carrying such CARs are generally referred to as CAR-T cells or CAR-T lymphocytes. However, while CARs can effectively target T lymphocytes to specific tumor-associated or tumor-specific antigens, they can also target normal, healthy cells that also express such antigens. Described herein are modified chimeric receptors that overcome this shortcoming of current CAR designs.

在一個態樣中，本文提供嵌合抗原受體(CAR)，其包含：(a)第一多肽，其包含cereblon或其官能性部分；及(b)第二多肽，其包含cereblon相關蛋白或其官能性部分，其中第一多肽或第二多肽或多肽二者包含CAR之額外組分，諸如抗原結合域、跨膜域、細胞信號傳導域及/或共刺激域。當CAR之第一多肽及第二多肽在cereblon結合化合物(例如，如本文所描述)之存在下在免疫細胞(例如，T淋巴球)中一起表現時，第一多肽之cereblon (或其官能性部分，例如，如本文所描述)及第二多肽之cereblon相關蛋白(或其官能性部分，例如，如本文所描述)結合cereblon結合化合物，使得形成具有CAR官能的異二聚體。因此，本文所描述之CAR之活性(例如，活體內活性)可藉由使表現CAR之第一多肽及第二多肽的細胞(例如，經工程改造以表現該等CAR之T淋巴球)與cereblon結合化合物接觸來選擇性地控制。當在免疫細胞中表現之CAR與cereblon結合化合物接觸且CAR與抗原(例如，腫瘤相關抗原或腫瘤特異性抗原)結合時，CAR傳輸原代信號及共刺激信號兩者，由此活化免疫細胞。 在一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其包含抗原結合域、跨膜域及cereblon或其官能性部分，其中該cereblon (或其官能性部分)能夠與cereblon結合化合物結合；以及(b)第二多肽，其包含跨膜域、cereblon相關蛋白或其官能性部分及原代細胞信號傳導域，其中該cereblon相關蛋白(或其官能性部分)能夠結合cereblon結合化合物；其中在該cereblon結合化合物之存在下，該第一多肽及該第二多肽形成異二聚體。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一特定實施例中，該cereblon結合化合物為泊利度胺（pomalidomide） (4-胺基-2-[(3RS)-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，該cereblon結合化合物為沙立度胺(thalidomide) ((RS)-2-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，該cereblon結合化合物為來那度胺(lenalidomide) (3-(4-胺基-1-側氧基-1,3-二氫-2H-異吲哚-2-基)哌啶-2,6-二酮)。在另一特定實施例中，該cereblon結合化合物為3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮。在另一特定實施例中，該cereblon結合化合物為3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域及cereblon或其官能性部分；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon相關蛋白或其官能性部分及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon或其官能性部分及跨膜域；及(b)第二多肽，其按自N端至C端之順序包含cereblon相關蛋白或其官能性部分、跨膜域及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其包含抗原結合域、跨膜域及cereblon相關蛋白或其官能性部分，其中該cereblon相關蛋白(或其官能性部分)能夠與cereblon結合化合物結合；及(b)第二多肽，其包含跨膜域、cereblon或其官能性部分及原代細胞信號傳導域，其中該cereblon (或其官能性部分)能夠結合cereblon結合化合物；其中在該cereblon結合化合物之存在下，該第一多肽及該第二多肽形成異二聚體。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在一特定實施例中，該cereblon結合化合物為泊利度胺(4-胺基-2-[(3RS)-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，該cereblon結合化合物為沙立度胺((RS)-2-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，該cereblon結合化合物為來那度胺(3-(4-胺基-1-側氧基-1,3-二氫-2H-異吲哚-2-基)哌啶-2,6-二酮)。在另一特定實施例中，該cereblon結合化合物為3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮。在另一特定實施例中，該cereblon結合化合物為3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域及cereblon相關蛋白或其官能性部分；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon或其官能性部分及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon相關蛋白或其官能性部分及跨膜域；及(b)第二多肽，其按自N端至C端之順序包含cereblon或其官能性部分、跨膜域及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域、cereblon或其官能性部分及原代細胞信號傳導域；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon相關蛋白或其官能性部分及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon或其官能性部分、跨膜域及包含原代細胞信號傳導域之多肽；及(b)第二多肽，其按自N端至C端之順序包含cereblon相關蛋白或其官能性部分、跨膜域及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域、cereblon相關蛋白或其官能性部分及原代細胞信號傳導域；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon或其官能性部分及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon相關蛋白或其官能性部分、跨膜域及包含原代細胞信號傳導域的多肽；及(b)第二多肽，其按自N端至C端之順序包含cereblon或其官能性部分、跨膜域及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在某些實施例中，當本文所描述之CAR之第一多肽或第二多肽包含原代細胞信號傳導域時，該多肽為CD3ζ。在一特定實施例中，該細胞信號傳導域為人。 在某些實施例中，當本文所描述之CAR之第一多肽或第二多肽包含原代細胞信號傳導域時，該原代細胞信號傳導域為基於免疫受體酪胺酸的活化基元(ITAM)原代細胞信號傳導域或包含該基於免疫受體酪胺酸的活化基元原代細胞信號傳導域。在一特定實施例中，該ITAM衍生自以下中之一或多者：FcRγ、FcRβ、CD3ζ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD20、CD79a、CD79b、CD278 (ICOS)、FcεRI、CD66d、DAP10及/或DAP12。在一特定實施例中，該細胞信號傳導域為人。 在某些實施例中，當本文所描述之CAR之第一多肽及/或第二多肽包含共刺激域時，共刺激域衍生自以下中之一或多者：CD28、4-1BB (CD137)、OX40、活化NK細胞受體、BTLA、Toll配位體受體、CD2、CD7、CD27、CD30、CD40、CDS、ICAM-L LFA-1 (CD11a/CD18)、B7-H3、CDS、ICAM-1、ICOS (CD278)、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、NKG2C、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、DAP10、DAP12、CD83之配位體、MHC I類分子、TNF受體蛋白、免疫球蛋白類蛋白、細胞介素受體、整合素及/或信號傳導淋巴球性活化分子。在一特定實施例中，該共刺激域為人。 在某些實施例中，本文所提供之CAR之第一多肽及/或第二多肽的跨膜域包含來自以下之跨膜域：T細胞受體之α鏈、T細胞受體之β鏈、T細胞受體之ζ鏈、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154。在一特定實施例中，該跨膜域為人。 在某些實施例中，本文所描述之CAR的抗原結合域包含受體。 在某些實施例中，本文所描述之CAR的抗原結合域包含抗體或其結合片段。在一特定實施例中，該抗體之結合片段為單鏈Fv片段(scFv)。 在某些實施例中，由本文所描述之CAR的抗原結合域所結合之抗原為腫瘤細胞上之抗原。在一特定實施例中，該抗原為實體腫瘤細胞之抗原。在另一特定實施例中，該抗原為血癌細胞之抗原。 在另一特定實施例中，由本文所描述之CAR的抗原結合域所結合之抗原為腫瘤相關抗原(TAA)或腫瘤特異性抗原(TSA)。在一特定實施例中，TAA或TSA為以下或其片段中之一或多者：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y (Lewis Y)、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在另一態樣中，本文提供對本文所描述之CAR進行編碼之核酸，即，對本文所描述之CAR之第一多肽進行編碼的核酸及對本文所描述之CAR之第二多肽進行編碼的核酸。在某些實施例中，本文所描述之CAR的第一多肽由第一核酸(聚核苷酸)編碼且本文所描述之CAR的第二多肽由第二核酸(聚核苷酸)編碼。在一特定實施例中，本文提供對本文所描述之CAR的第一多肽及第二多肽兩者進行編碼之核酸(聚核苷酸)。 在某些實施例中，本文所描述之CAR多肽編碼核酸包含於核酸載體內。在一特定實施例中，該載體為反轉錄病毒載體。在另一特定實施例中，該載體為慢病毒載體。 在某些實施例中，本文所描述之CAR多肽編碼核酸可操作地連接至啟動子。在一特定實施例中，該啟動子為T細胞特異性啟動子、自然殺手(NK)細胞特異性啟動子、作用於T細胞或NK細胞內之誘導型啟動子或組成型啟動子。 在另一態樣中，本文提供包含本文所描述之CAR編碼核酸及/或載體的細胞(在本文中被稱作「CAR細胞」)。該等細胞包括原核(例如，細菌)細胞及真核(例如，哺乳動物)細胞。在一特定實施例中，本文提供包含本文所描述之CAR的T細胞，例如，CD4+、CD+ T細胞、T效應細胞或T記憶細胞。在另一特定實施例中，本文提供包含本文所描述之CAR的自然殺手細胞。 本文所提供之CAR細胞(例如，包含本文所描述之CAR編碼核酸或表現本文所描述之CAR (亦即，表現本文所描述之CAR的第一多肽及第二多肽)之T細胞)可在與(i)抗原(即，由CAR之抗原結合域識別之抗原)及(ii)cereblon結合化合物接觸時經活化，CAR對該抗原具有特異性。因此，在另一態樣中，本文提供用於活化包含及/或表現本文所描述之CAR的細胞(例如，T細胞或NK細胞)之方法，該等方法包含使該細胞與結合CAR之抗原結合域的抗原接觸且使細胞與cereblon結合化合物進一步接觸。在一特定實施例中，該細胞在活體內與該抗原及該cereblon結合化合物接觸，即，接觸發生於在向個體投與該細胞之後。在另一特定實施例中，向個體投與該細胞且給定指定時段來定位並與抗原接觸，CAR對該抗原具有特異性，接著向個體投與cereblon結合化合物。 在某些實施例中，本文所提供之CAR細胞進一步包含人工細胞死亡多肽，該人工細胞死亡多肽包含細胞凋亡誘導域及二聚域，其中該人工細胞死亡多肽可使用二聚劑二聚化，且其中當人工細胞死亡多肽經二聚化時，該多肽在該細胞中產生細胞凋亡誘導信號。在一特定實施例中，該二聚劑為雷帕黴素(rapamycin)或雷帕黴素之類似物(雷帕黴素之類似物(rapalog))。在另一特定實施例中，該二聚劑為AP1903 (rimiducid)。在另一特定實施例中，該二聚劑不為cereblon結合化合物。在一特定實施例中，該二聚域為FK結合域或其類似物。在另一特定實施例中，該二聚劑為與該FK結合域結合之抗體。 在另一態樣中，本文提供用於殺滅表現由本文所描述之CAR之抗原結合域所結合的抗原之靶細胞的方法，其中該等方法包含(i)使該等靶細胞與包含/表現本文所描述之CAR的細胞(例如，T細胞或NK細胞)接觸及(ii)使該CAR表現細胞與cereblon結合化合物接觸，其中在該抗原及該cereblon結合化合物之存在下，CAR表現細胞變得活化。在一特定實施例中，該靶細胞為癌細胞，例如血癌細胞或實體腫瘤細胞。在另一特定實施例中，該靶細胞表現以下抗原或其抗原片段中之一或多者：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在另一態樣中，本文提供治療癌症之方法，該等方法包含：(i)向個體(例如，人類個體)投與本文所描述之CAR細胞(例如，T細胞或NK細胞)群體，該CAR細胞群體包含/表現本文所描述之CAR (例如，包含本文所描述之CAR編碼核酸或表現本文所描述之CAR)，其中該CAR包含對癌抗原(例如，TSA或TAA)具有特異性之抗原結合域；及(ii)向個體投與包含cereblon結合化合物之組合物。在一特定實施例中，首先向個體投與該細胞群體，接著在投與細胞群體後之特定時段處(例如，在投與細胞群體後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，投與包含cereblon結合化合物之組合物。在一特定實施例中，由該CAR結合之該抗原為：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在一特定實施例中，根據本文所描述之治療癌症之方法而向個體投與之cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 可根據本文所描述之治療方法治療之癌症的非限制性清單包括：淋巴瘤、白血病、肺癌、乳癌、前列腺癌、腎上腺皮質癌瘤、甲狀腺癌瘤、鼻咽癌瘤、黑素瘤、皮膚癌瘤、結腸直腸癌、硬纖維腫瘤、促結締組織增生性小圓細胞腫瘤(desmoplastic small round cell tumor)、內分泌腫瘤、尤文氏肉瘤(Ewing sarcoma)、周邊原始神經外胚層瘤、固體生殖細胞腫瘤、肝母細胞瘤、神經母細胞瘤、非橫紋肌肉瘤軟組織肉瘤、骨肉瘤、視網膜母細胞瘤、橫紋肌肉瘤、威爾姆斯腫瘤(Wilms tumor)、神經膠瘤、神經膠母細胞瘤、黏液瘤、纖維瘤及脂肪瘤。例示性淋巴瘤及白血病包括(但不限於)：慢性淋巴球性白血病(小淋巴球性淋巴瘤)、B細胞前淋巴球性白血病、淋巴漿細胞性淋巴瘤、瓦爾登斯特倫巨球蛋白血症(Waldenström macroglobulinemia)、脾邊緣區淋巴瘤、漿細胞骨髓瘤、漿細胞瘤、結外邊緣區B細胞淋巴瘤、MALT淋巴瘤、結邊緣區B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、T淋巴球前淋巴球性白血病、T淋巴球大顆粒淋巴球性白血病、侵襲性NK細胞白血病、成人T淋巴球白血病/淋巴瘤、結外NK/T淋巴球淋巴瘤、鼻型、腸病型T淋巴球淋巴瘤、肝脾T淋巴球淋巴瘤、母細胞性NK細胞淋巴瘤、蕈樣黴菌病、塞紮萊症候群(Sezary syndrome)、原發性皮膚多形性大細胞淋巴瘤、淋巴瘤樣丘疹病、血管免疫母細胞T淋巴球淋巴瘤、周邊T淋巴球淋巴瘤(未指定)、多形性大細胞淋巴瘤、霍奇金淋巴瘤(Hodgkin lymphoma)或非霍奇金淋巴瘤(non-Hodgkin lymphoma)。 在另一態樣中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分)；及(b)第二多肽，其包含細胞凋亡誘導域(或其官能性部分)及Aiolos (或其官能性部分)，其中該cereblon (或其官能性部分)及該Aiolos (或其官能性部分)兩者均能夠結合cereblon結合化合物，且其中該第一多肽及該第二多肽在該cereblon結合化合物之存在下二聚化以產生細胞凋亡誘導信號。在一特定實施例中，該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分))；及(b)第二多肽，其包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分)。在一特定實施例中，該第二多肽包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分))。在一特定實施例中，該cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含胞外域(包含cereblon (或其官能性部分))、跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分))；及(b)第二多肽，其包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分)。在另一特定實施例中，該第二多肽包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分))。在另一特定實施例中，該第二多肽包含跨膜蛋白，該跨膜蛋白包含胞外域(包含cereblon相關蛋白(或其官能性部分))、跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分))。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分)；及(b)第二多肽，其包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分))。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分)；及(b)第二多肽，其包含跨膜蛋白，該跨膜蛋白包含胞外域(包含cereblon相關蛋白(或其官能性部分))、跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分))。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 在某些實施例中，本文提供可二聚化人工細胞死亡受體之細胞凋亡誘導域為凋亡蛋白酶。在一特定實施例中，該凋亡蛋白酶為凋亡蛋白酶9、凋亡蛋白酶8或凋亡蛋白酶3。 在另一態樣中，本文提供對本文所描述之可二聚化人工細胞死亡受體進行編碼的核酸，即對本文所描述之可二聚化人工細胞死亡受體之第一多肽進行編碼的核酸及對本文所描述之可二聚化人工細胞死亡受體之第二多肽進行編碼的核酸。在某些實施例中，本文所描述之可二聚化人工細胞死亡受體之第一多肽由第一核酸(聚核苷酸)編碼且本文所描述之可二聚化人工細胞死亡受體之第二多肽由第二核酸(聚核苷酸)編碼。在一特定實施例中，本文提供對本文所描述之可二聚化人工細胞死亡受體之第一多肽及第二多肽兩者進行編碼的核酸(聚核苷酸)。 在某些實施例中，本文所描述之可二聚化人工細胞死亡受體編碼核酸包含於核酸載體內。在一特定實施例中，該載體為反轉錄病毒載體。在另一特定實施例中，該載體為慢病毒載體。 在某些實施例中，本文所描述之可二聚化人工細胞死亡受體編碼核酸可操作地連接至啟動子。在一特定實施例中，該啟動子為T細胞特異性啟動子、自然殺手(NK)細胞特異性啟動子、作用於T細胞或NK細胞內之誘導型啟動子或組成型啟動子。 在另一態樣中，本文提供包含本文所描述之可二聚化人工細胞死亡受體編碼核酸及/或本文所描述之載體的細胞(在本文中被稱作「細胞死亡受體細胞」)。該等細胞包括原核(例如，細菌)細胞及真核(例如，哺乳動物)細胞。在一特定實施例中，本文提供包含本文所描述之可二聚化人工細胞死亡受體的T細胞，例如CD4+、CD8+ T細胞、T效應細胞或T記憶細胞。在另一特定實施例中，本文提供包含本文所描述之可二聚化人工細胞死亡受體的自然殺手細胞。 本文所提供之細胞死亡受體細胞(例如，包含本文所描述之可二聚化人工細胞死亡受體編碼核酸或表現本文所描述之可二聚化人工細胞死亡受體(亦即，表現本文所描述之可二聚化人工細胞死亡受體之第一多肽及第二多肽)的T細胞或NK細胞)可在與cereblon結合化合物接觸時(例如，在與泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮接觸時)經誘導以經受細胞凋亡。 在某些實施例中，本文所提供之細胞死亡受體細胞進一步包含CAR，例如第一代CAR、第二代CAR或第三代CAR。在一特定實施例中，該CAR包含兩個或多於兩個胞外抗原靶向域。在另一特定實施例中，該CAR包含與為T細胞活性之負調節劑之介白素結合的胞外域，及來自為T細胞活性之正調節劑之介白素受體的胞內域。在另一特定實施例中，藉由使細胞與cereblon結合化合物(例如，泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮)接觸而在包含人工細胞死亡受體及CAR的細胞中誘導細胞凋亡。 In one aspect, provided herein is a chimeric antigen receptor (CAR) comprising: (a) a first polypeptide comprising cereblon or a functional portion thereof; and (b) a second polypeptide comprising a cereblon-related A protein or functional portion thereof, wherein the first polypeptide or the second polypeptide or both polypeptides comprise additional components of the CAR, such as an antigen binding domain, a transmembrane domain, a cell signaling domain and/or a co-stimulatory domain. When the first and second polypeptides of the CAR are expressed together in an immune cell (e.g., T lymphocyte) in the presence of a cereblon-binding compound (e.g., as described herein), the cereblon of the first polypeptide (or A functional portion thereof, e.g., as described herein) and a cereblon-associated protein of a second polypeptide (or a functional portion thereof, e.g., as described herein) bind to the cereblon-binding compound such that a heterodimer with CAR functionality is formed . Thus, the activity (e.g., in vivo activity) of the CARs described herein can be determined by making cells expressing the first and second polypeptides of the CAR (e.g., T lymphocytes engineered to express the CARs) Selective control is achieved by exposure to cereblon-binding compounds. When a CAR expressed in an immune cell is contacted with a cereblon-binding compound and the CAR binds to an antigen (eg, a tumor-associated antigen or a tumor-specific antigen), the CAR transmits both primary and co-stimulatory signals, thereby activating the immune cell. In a specific embodiment, provided herein is a CAR comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and cereblon or a functional portion thereof, wherein the cereblon (or a functional portion thereof) capable of binding to a cereblon-binding compound; and (b) a second polypeptide comprising a transmembrane domain, a cereblon-associated protein or a functional portion thereof, and a primary cell signaling domain, wherein the cereblon-associated protein (or a functional portion thereof) Capable of binding a cereblon-binding compound; wherein in the presence of the cereblon-binding compound, the first polypeptide and the second polypeptide form a heterodimer. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the cereblon-binding compound is pomalidomide (4-amino-2-[(3RS)-(2,6-dioxahexahydropyridin-3-yl)-1H -isoindole-1,3(2H)-dione). In another specific embodiment, the cereblon-binding compound is thalidomide ((RS)-2-(2,6-dioxahexahydropyridin-3-yl)-1H-isoindole-1 ,3(2H)-diketone). In another specific embodiment, the cereblon-binding compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2- base) piperidine-2,6-dione). In another specific embodiment, the cereblon-binding compound is 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-iso Indol-2-yl]-piperidine-2,6-dione. In another specific embodiment, the cereblon binding compound is 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl) Oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and cereblon or a functional part thereof in order from the N-terminus to the C-terminus; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, a cereblon-associated protein or a functional part thereof, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, cereblon or a functional part thereof, and a transmembrane domain in order from the N-terminus to the C-terminus; and (b) a second polypeptide comprising, in order from the N-terminus to the C-terminus, a cereblon-related protein or a functional part thereof, a transmembrane domain, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, provided herein is a CAR comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and a cereblon-related protein or a functional portion thereof, wherein the cereblon-related protein (or a functional portion thereof) capable of binding to a cereblon-binding compound; and (b) a second polypeptide comprising a transmembrane domain, cereblon, or a functional portion thereof, and a primary cell signaling domain, wherein the cereblon (or functional portion thereof ) is capable of binding a cereblon-binding compound; wherein in the presence of the cereblon-binding compound, the first polypeptide and the second polypeptide form a heterodimer. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In a specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In a specific embodiment, the cereblon-binding compound is polilidomide (4-amino-2-[(3RS)-(2,6-dioxahexahydropyridin-3-yl)-1H-isoindole -1,3(2H)-dione). In another specific embodiment, the cereblon-binding compound is thalidomide ((RS)-2-(2,6-dioxahexahydropyridin-3-yl)-1H-isoindole-1,3( 2H)-diketone). In another specific embodiment, the cereblon-binding compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piper pyridine-2,6-dione). In another specific embodiment, the cereblon-binding compound is 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-iso Indol-2-yl]-piperidine-2,6-dione. In another specific embodiment, the cereblon binding compound is 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl) Oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and a cereblon-related protein or functionalities thereof in order from the N-terminus to the C-terminus and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, cereblon or a functional portion thereof, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In a specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising, in order from N-terminus to C-terminus, an antigen-binding domain, a cereblon-related protein or a functional part thereof, and a transmembrane and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, cereblon or a functional portion thereof, a transmembrane domain, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, cereblon or a functional part thereof in order from N-terminus to C-terminus, and a primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, a cereblon-associated protein or a functional portion thereof, and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising, in order from N-terminus to C-terminus, an antigen-binding domain, cereblon or a functional part thereof, a transmembrane domain, and A polypeptide comprising a primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a cereblon-associated protein or a functional portion thereof, a transmembrane domain and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, a cereblon-related protein, or functionalities thereof in order from the N-terminus to the C-terminus part and primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, cereblon or a functional portion thereof, and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising, in order from the N-terminus to the C-terminus, an antigen-binding domain, a cereblon-related protein or a functional part thereof, a transmembrane domain and a polypeptide comprising a primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, cereblon or a functional portion thereof, a transmembrane domain and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In certain embodiments, when the first polypeptide or the second polypeptide of a CAR described herein comprises a primary cell signaling domain, the polypeptide is CD3ζ. In a specific embodiment, the cell signaling domain is human. In certain embodiments, when the first polypeptide or the second polypeptide of the CAR described herein comprises a primary cell signaling domain, the primary cell signaling domain is an immunoreceptor tyrosine-based activator Element (ITAM) primary cell signaling domain or a primary cell signaling domain comprising the immunoreceptor tyrosine-based activation motif. In a specific embodiment, the ITAM is derived from one or more of the following: FcRγ, FcRβ, CD3ζ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD20, CD79a, CD79b, CD278 (ICOS), FcεRI, CD66d, DAP10 and/or DAP12. In a specific embodiment, the cell signaling domain is human. In certain embodiments, when the first polypeptide and/or the second polypeptide of the CAR described herein comprises a co-stimulatory domain, the co-stimulatory domain is derived from one or more of the following: CD28, 4-1BB ( CD137), OX40, activated NK cell receptor, BTLA, Toll ligand receptor, CD2, CD7, CD27, CD30, CD40, CDS, ICAM-L LFA-1 (CD11a/CD18), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4 , VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18 , LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG /Cbp, CD19a, DAP10, DAP12, ligands of CD83, MHC class I molecules, TNF receptor proteins, immunoglobulin proteins, interleukin receptors, integrins and/or signal transduction lymphocyte activation molecules. In a specific embodiment, the co-stimulatory domain is human. In certain embodiments, the transmembrane domain of the first polypeptide and/or the second polypeptide of the CAR provided herein comprises a transmembrane domain from the following: alpha chain of T cell receptor, beta of T cell receptor chain, zeta chain of T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154. In a specific embodiment, the transmembrane domain is human. In certain embodiments, the antigen binding domain of a CAR described herein comprises a receptor. In certain embodiments, the antigen binding domain of a CAR described herein comprises an antibody or binding fragment thereof. In a specific embodiment, the binding fragment of the antibody is a single chain Fv fragment (scFv). In certain embodiments, the antigen bound by the antigen binding domain of a CAR described herein is an antigen on a tumor cell. In a specific embodiment, the antigen is an antigen of a solid tumor cell. In another specific embodiment, the antigen is an antigen of a blood cancer cell. In another specific embodiment, the antigen bound by the antigen binding domain of the CAR described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In a specific embodiment, TAA or TSA is one or more of the following or fragments thereof: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA) , BAFF, B-lymphoma cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor) , CD28, CD30 (TNFRSF8), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX , GD2, GD3, Glycoprotein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor, IGF -I, IgG1, IL-6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM , λ light chain, Lewis Y (Lewis Y), mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC- 1C, PDGF-R a, PDL192, phosphatidylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, Tenascin C, TGF β2, TGF-I3, TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In another aspect, provided herein are nucleic acids encoding a CAR described herein, i.e., a nucleic acid encoding a first polypeptide of a CAR described herein and a nucleic acid encoding a second polypeptide of a CAR described herein. encoding nucleic acid. In certain embodiments, a first polypeptide of a CAR described herein is encoded by a first nucleic acid (polynucleotide) and a second polypeptide of a CAR described herein is encoded by a second nucleic acid (polynucleotide) . In a specific embodiment, provided herein are nucleic acids (polynucleotides) encoding both the first polypeptide and the second polypeptide of the CAR described herein. In certain embodiments, a CAR polypeptide-encoding nucleic acid described herein is contained within a nucleic acid vector. In a specific embodiment, the vector is a retroviral vector. In another specific embodiment, the vector is a lentiviral vector. In certain embodiments, a CAR polypeptide-encoding nucleic acid described herein is operably linked to a promoter. In a specific embodiment, the promoter is a T cell specific promoter, a natural killer (NK) cell specific promoter, an inducible promoter acting in T cells or NK cells, or a constitutive promoter. In another aspect, provided herein are cells comprising the CAR-encoding nucleic acids and/or vectors described herein (referred to herein as "CAR cells"). Such cells include prokaryotic (eg, bacterial) cells and eukaryotic (eg, mammalian) cells. In a specific embodiment, provided herein are T cells, e.g., CD4+, CD+ T cells, T effector cells, or T memory cells, comprising a CAR described herein. In another specific embodiment, provided herein are natural killer cells comprising a CAR described herein. A CAR cell provided herein (e.g., a T cell comprising a CAR-encoding nucleic acid described herein or expressing a CAR described herein (i.e., expressing a first polypeptide and a second polypeptide of a CAR described herein) can be Activated upon contact with (i) an antigen (ie, the antigen recognized by the antigen-binding domain of the CAR) and (ii) a cereblon-binding compound for which the CAR is specific. Accordingly, in another aspect, provided herein are methods for activating cells (e.g., T cells or NK cells) comprising and/or expressing a CAR described herein comprising contacting the cell with an antigen that binds the CAR. The antigen binding domain is contacted and the cell is further contacted with the cereblon binding compound. In a specific embodiment, the cell is contacted with the antigen and the cereblon-binding compound in vivo, ie, contacting occurs after administration of the cell to the individual. In another specific embodiment, the cells are administered to the individual and given a specified period of time to locate and contact the antigen for which the CAR is specific, followed by administration of the cereblon-binding compound to the individual. In certain embodiments, the CAR cells provided herein further comprise an artificial cell death polypeptide comprising an apoptosis-inducing domain and a dimerization domain, wherein the artificial cell death polypeptide can be dimerized using a dimerizing agent , and wherein when the artificial cell death polypeptide is dimerized, the polypeptide produces an apoptosis-inducing signal in the cell. In a particular embodiment, the dimerizing agent is rapamycin or an analog of rapamycin (rapalog). In another specific embodiment, the dimerizing agent is AP1903 (rimiducid). In another specific embodiment, the dimerizing agent is not a cereblon binding compound. In a specific embodiment, the dimerization domain is a FK binding domain or an analog thereof. In another specific embodiment, the dimerizing agent is an antibody that binds to the FK binding domain. In another aspect, provided herein are methods for killing target cells expressing an antigen bound by an antigen-binding domain of a CAR described herein, wherein the methods comprise (i) combining the target cells with comprising/ contacting a cell (e.g., a T cell or NK cell) expressing a CAR described herein and (ii) contacting the CAR-expressing cell with a cereblon-binding compound, wherein in the presence of the antigen and the cereblon-binding compound, the CAR-expressing cell becomes get activated. In a specific embodiment, the target cell is a cancer cell, such as a blood cancer cell or a solid tumor cell. In another specific embodiment, the target cell expresses one or more of the following antigens or antigenic fragments thereof: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA), BAFF, B-lymphoma cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET , CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX, GD2, GD3, Glycoprotein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor IGF-I, IgG1, IL-6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM, λ light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C , PDGF-R a, PDL192, phosphatidylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tendon Protein C, TGF β2, TGF-I3, TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In another aspect, provided herein are methods of treating cancer, the methods comprising: (i) administering to an individual (eg, a human individual) a population of CAR cells (eg, T cells or NK cells) described herein, the The CAR cell population comprises/expresses a CAR described herein (e.g., comprises a CAR-encoding nucleic acid described herein or expresses a CAR described herein), wherein the CAR comprises an antigen specific for a cancer antigen (e.g., TSA or TAA) a binding domain; and (ii) administering to the individual a composition comprising a cereblon binding compound. In a particular embodiment, the cell population is administered to the individual first, and then at a specified time period after administration of the cell population (e.g., 30 minutes, 1 hour, 6 hours, 12 hours, 1 hour after administration of the cell population). day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week), the composition comprising the cereblon-binding compound is administered. In a specific embodiment, the antigen bound by the CAR is: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA), BAFF, B-lymphoid Tumor cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor), CD28, CD30 (TNFRSF8 ), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX, GD2, GD3, sugar Protein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, IL -6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM, lambda light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C, PDGF-R a, PDL192, phospholipids Acylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tenascin C, TGF β2, TGF-I3 , TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In a specific embodiment, the cereblon-binding compound administered to an individual according to the methods of treating cancer described herein is polilidomide, thalidomide, lenalidomide, 3-[4-(4- Lin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4 -((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl ) piperidine-2,6-dione. A non-limiting list of cancers that may be treated according to the methods of treatment described herein include: lymphoma, leukemia, lung cancer, breast cancer, prostate cancer, adrenocortical carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, melanoma, skin cancer tumor, colorectal cancer, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing sarcoma, peripheral primitive neuroectodermal tumor, solid germ cell tumor, Hepatoblastoma, neuroblastoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioma, glioblastoma, myxoma, Fibroids and lipomas. Exemplary lymphomas and leukemias include (but are not limited to): chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulin Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle Cell lymphoma, Diffuse large B-cell lymphoma, Mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, Burkitt's lymphoma, T Prolymphocytic leukemia, T lymphocytic large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T lymphocytic leukemia/lymphoma, extranodal NK/T lymphocytic lymphoma, nasal type, enteropathy type T Lymphocytic lymphoma, hepatosplenic T lymphocytic lymphoma, NK cell lymphoma, mycosis fungoides, Sezary syndrome, primary cutaneous pleomorphic large cell lymphoma, lymphomatoid Papulosis, angioimmunoblastic T lymphocytic lymphoma, peripheral T lymphocytic lymphoma (unspecified), pleomorphic large cell lymphoma, Hodgkin lymphoma, or non-Hodgkin lymphoma (non-Hodgkin lymphoma) -Hodgkin lymphoma). In another aspect, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon (or a functional portion thereof) and functional portion); and (b) a second polypeptide comprising an apoptosis-inducing domain (or a functional portion thereof) and Aiolos (or a functional portion thereof), wherein the cereblon (or a functional portion thereof) and the Both Aiolos (or a functional portion thereof) are capable of binding a cereblon-binding compound, and wherein the first polypeptide and the second polypeptide dimerize in the presence of the cereblon-binding compound to generate an apoptosis-inducing signal. In a particular embodiment, the cereblon-binding compound is polilidomide, thalidomide, lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)- 1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4-((4-((4-(2,4- Difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In a specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising a transmembrane domain and an intracellular domain ( comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon (or a functional portion thereof); and (b) a second polypeptide comprising an apoptosis-inducing domain (or a functional portion thereof) and a cereblon-related Proteins (or functional parts thereof). In a specific embodiment, the second polypeptide comprises a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof) and a cereblon-associated protein (or a functional portion thereof) functional part)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising an extracellular domain (comprising cereblon (or Its functional part)), transmembrane domain and intracellular domain (comprising apoptosis-inducing domain (or its functional part)); and (b) the second polypeptide, it comprises cell apoptosis-inducing domain (or its functional part) Sexual parts) and cereblon-related proteins (or functional parts thereof). In another specific embodiment, the second polypeptide comprises a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof) and a cereblon-associated protein (or its functional part)). In another specific embodiment, the second polypeptide comprises a transmembrane protein comprising an extracellular domain (comprising cereblon-associated protein (or a functional portion thereof)), a transmembrane domain and an intracellular domain (comprising apoptosis death-inducing domain (or a functional portion thereof)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising an apoptosis-inducing domain (or its functional portion) and cereblon (or its functional portion); and (b) a second polypeptide comprising a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain ( or functional parts thereof) and cereblon-related proteins (or functional parts thereof)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon (or a functional portion thereof); and (b) a second polypeptide comprising a transmembrane protein comprising an extracellular domain (comprising a cereblon-associated protein (or a functional portion thereof)) , a transmembrane domain, and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In certain embodiments, provided herein is an apoptosis-inducing domain of a dimerizable artificial cell death receptor that is an apoptotic protease. In a specific embodiment, the caspase is caspase 9, caspase 8 or caspase 3. In another aspect, provided herein is a nucleic acid encoding a dimerizable artificial cell death receptor described herein, that is, encoding a first polypeptide of a dimerizable artificial cell death receptor described herein and nucleic acids encoding the second polypeptide of the dimerizable artificial cell death receptor described herein. In certain embodiments, the first polypeptide of the dimerizable artificial cell death receptor described herein is encoded by a first nucleic acid (polynucleotide) and the dimerizable artificial cell death receptor described herein The second polypeptide is encoded by a second nucleic acid (polynucleotide). In a specific embodiment, provided herein are nucleic acids (polynucleotides) encoding both the first and second polypeptides of the dimerizable artificial cell death receptors described herein. In certain embodiments, a dimerizable artificial cell death receptor-encoding nucleic acid described herein is contained within a nucleic acid vector. In a specific embodiment, the vector is a retroviral vector. In another specific embodiment, the vector is a lentiviral vector. In certain embodiments, a dimerizable artificial cell death receptor-encoding nucleic acid described herein is operably linked to a promoter. In a specific embodiment, the promoter is a T cell specific promoter, a natural killer (NK) cell specific promoter, an inducible promoter acting in T cells or NK cells, or a constitutive promoter. In another aspect, provided herein are cells comprising the dimerizable artificial cell death receptor-encoding nucleic acids described herein and/or the vectors described herein (referred to herein as "cell death receptor cells") . Such cells include prokaryotic (eg, bacterial) cells and eukaryotic (eg, mammalian) cells. In a specific embodiment, provided herein are T cells, eg, CD4+, CD8+ T cells, T effector cells, or T memory cells, comprising a dimerizable artificial cell death receptor described herein. In another specific embodiment, provided herein are natural killer cells comprising a dimerizable artificial cell death receptor described herein. A cell death receptor cell provided herein (e.g., comprising a dimerizable artificial cell death receptor encoding nucleic acid described herein or expressing a dimerizable artificial cell death receptor described herein (i.e., expressing a nucleic acid described herein) T cells or NK cells described as capable of dimerizing the first polypeptide and the second polypeptide of the artificial cell death receptor) can be in contact with cereblon-binding compounds (for example, in the presence of polilidomide, thalidomide, Amine, lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl ]-piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione) are induced to undergo apoptosis. In certain embodiments, the cell death recipient cells provided herein further comprise a CAR, such as a first generation CAR, a second generation CAR, or a third generation CAR. In a specific embodiment, the CAR comprises two or more extracellular antigen targeting domains. In another specific embodiment, the CAR comprises an extracellular domain that binds interleukin, which is a negative regulator of T cell activity, and an intracellular domain from an interleukin receptor, which is a positive regulator of T cell activity. In another specific embodiment, the compound (e.g., polilidomide, thalidomide, lenalidomide, 3-[4-(4-morpholin-4-ylmethyl -Benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4-((4-(( 4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)piperidine-2,6 -diketone) to induce apoptosis in cells containing artificial cell death receptors and CARs.

藉由表現CAR之治療性免疫細胞介導的靶向但脫靶腫瘤效應(其可能產生毒性)可藉由在為活化所需之原代信號及共刺激信號兩者的此類細胞可調節CAR中表現而減小或消除。如本文所揭示，此分離係經由使用包含兩個人工多肽之CAR而完成，其中：(i)第一多肽包含cereblon (或其官能性部分)且第二多肽包含cereblon相關蛋白(或其官能性部分)；(ii)在兩個多肽上劃分為活化所需之CAR之組分；及(iii) CAR在結合cereblon與cereblon相關蛋白的cereblon結合化合物之存在下經活化。 CAR介導之靶向但脫靶腫瘤效應亦可藉由使用可允許視需要殺滅表現此類受體之細胞的二聚化人工細胞死亡受體來減小或消除。如本文所描述，此類可二聚化人工細胞死亡受體包含第一多肽(包含細胞凋亡誘導域及二聚域，例如cereblon (或其官能性部分))及第二多肽(包含細胞凋亡誘導域及補充二聚域，例如cereblon相關蛋白(或其官能性部分))。表現此類可二聚化人工細胞死亡受體之細胞可藉由使其與能夠二聚化第一多肽及第二多肽的cereblon結合化合物接觸而經誘導以經受細胞凋亡，且因此活化細胞凋亡誘導域。4.1. 嵌合抗原受體及其用途 4.1.1 嵌合抗原受體構建體 本文提供嵌合抗原受體(CAR)，其包含：(a)第一多肽，其包含cereblon或其官能性部分；及(b)第二多肽，其包含cereblon相關蛋白或其官能性部分，其中第一多肽或第二多肽或多肽兩者包含CAR之剩餘組分，諸如抗原結合域、跨膜域、細胞信號傳導域及/或共刺激域。當CAR之第一多肽及第二多肽在cereblon結合化合物之存在下在免疫細胞中一起表現(例如，在T淋巴球或自然殺手細胞中表現)時，第一多肽之cereblon (或其官能性部分)及第二多肽之該cereblon相關蛋白(或其官能性部分)結合cereblon結合化合物，使得形成具有CAR官能之異二聚體。因此，本文所描述之CAR之活性(例如，活體內活性)可藉由使表現CAR之第一多肽及第二多肽的細胞(例如，經工程改造以表現該等CAR之T淋巴球)與cereblon結合化合物接觸來選擇性地控制。如本文中所使用，「跨膜域」包括：穿過跨膜域，其中包含跨膜域之蛋白包含胞內域及胞外域兩者；及膜錨定域，其中包含跨膜域之蛋白包含胞內域但不包含胞外域。 在一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其包含抗原結合域、跨膜域及cereblon或其官能性部分，其中該cereblon (或其官能性部分)能夠與cereblon結合化合物結合；及(b)第二多肽，其包含跨膜域、cereblon相關蛋白或其官能性部分及原代細胞信號傳導域，其中該cereblon相關蛋白(或其官能性部分)能夠結合cereblon結合化合物；其中在該cereblon結合化合物之存在下，該第一多肽及該第二多肽形成異二聚體。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域及cereblon或其官能性部分；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon相關蛋白或其官能性部分及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon或其官能性部分及跨膜域；及(b)第二多肽，其按自N端至C端之順序包含cereblon相關蛋白或其官能性部分、跨膜域及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其包含抗原結合域、跨膜域及cereblon相關蛋白或其官能性部分，其中該cereblon相關蛋白(或其官能性部分)能夠與cereblon結合化合物結合；及(b)第二多肽，其包含跨膜域、cereblon或其官能性部分及原代細胞信號傳導域，其中該cereblon (或其官能性部分)能夠結合cereblon結合化合物；其中在該cereblon結合化合物之存在下，該第一多肽及該第二多肽形成異二聚體。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在一特定實施例中，該cereblon結合化合物為泊利度胺(4-胺基-2-[(3RS)-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，該cereblon結合化合物為沙立度胺((RS)-2-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，該cereblon結合化合物為來那度胺(3-(4-胺基-1-側氧基-1,3-二氫-2H-異吲哚-2-基)哌啶-2,6-二酮)。在另一特定實施例中，該cereblon結合化合物為3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮。在另一特定實施例中，該cereblon結合化合物為3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域及cereblon相關蛋白或其官能性部分；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon或其官能性部分及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon相關蛋白或其官能性部分及跨膜域；及(b)第二多肽，其按自N端至C端之順序包含cereblon或其官能性部分、跨膜域及原代T細胞信號傳導域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一特定實施例中，第一多肽包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域。在另一特定實施例中，第一多肽及第二多肽包含共刺激域。在另一特定實施例中，第一多肽包含共刺激域且第二多肽不包含共刺激域。在另一特定實施例中，第二多肽包含共刺激域且第一多肽不包含共刺激域。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域、cereblon或其官能性部分及原代細胞信號傳導域；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon相關蛋白或其官能性部分及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon或其官能性部分、跨膜域及包含原代細胞信號傳導域之多肽；及(b)第二多肽，其按自N端至C端之順序包含cereblon相關蛋白或其官能性部分、跨膜域及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、跨膜域、cereblon相關蛋白或其官能性部分及原代細胞信號傳導域；及(b)第二多肽，其按自N端至C端之順序包含跨膜域、cereblon或其官能性部分及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種CAR，其包含：(a)第一多肽，其按自N端至C端之順序包含抗原結合域、cereblon相關蛋白或其官能性部分、跨膜域及包含原代細胞信號傳導域的多肽；及(b)第二多肽，其按自N端至C端之順序包含cereblon或其官能性部分、跨膜域及共刺激域。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。在另一實施例中，該cereblon (或其官能性部分)及該cereblon相關蛋白(或其官能性部分)均能夠結合cereblon結合化合物，其中該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。Cereblon 及 Cereblon 相關蛋白 本文所提供之CAR包含多肽，該等多肽包含cereblon或其官能性部分或cereblon相關蛋白(例如，Aiolos或Ikaros)或其官能性部分。如本文中所使用，將cereblon或cereblon相關蛋白之術語「官能性部分」定義為能夠結合cereblon結合化合物之cereblon或cereblon相關蛋白之一部分。在一些實施例中，cereblon或cereblon相關蛋白之官能性部分包含該cereblon或該cereblon相關蛋白之完整多肽編碼序列。在其他實施例中，cereblon或cereblon相關蛋白之官能性部分分別包含該cereblon或該cereblon相關蛋白之截斷。熟習此項技術者將識別需要用於維持官能及/或用於確保各蛋白與cereblon結合化合物之結合的各蛋白之組分。在其他實施例中，cereblon或cereblon相關蛋白之官能性部分分別包含衍生自該cereblon或該cereblon相關蛋白之肽序列。熟習此項技術者將識別需要用於維持官能及/或用於確保各蛋白與cereblon結合化合物之結合的各蛋白之組分。 在一些實施例中，本文所提供之CAR包含多肽，該多肽包含能夠結合cereblon結合化合物之cereblon或其官能性部分。在一些實施例中，本文所提供之CAR包含多肽，該多肽包含能夠結合cereblon結合化合物之cereblon相關蛋白(例如，Aiolos或Ikaros)或其官能性部分。在一些實施例中，本文所提供之CAR包含多肽，該多肽包含能夠結合cereblon結合化合物之Aiolos或其官能性部分。在特定實施例中，本文所提供之CAR包含：(i)第一多肽，其包含能夠結合cereblon結合化合物之cereblon或其官能性部分；及(ii)第二多肽，其包含能夠結合cereblon結合化合物之cereblon相關蛋白(例如，Aiolos或Ikaros)或其官能性部分。 Cereblon亦稱為蛋白「智力遲鈍非綜合型常染色體隱性2A」、CRBN、MRT2、MRT2A及AD-006。例如在Genbank Gene ID: 51185下提供編碼cereblon之例示性核酸。例如在Uniprot ID: Q96SW2-1下提供例示性cereblon胺基酸序列。熟習此項技術者將易於瞭解如何使用重組工程改造來製造並使用含cereblon之多肽。 如本文中所使用，術語「cereblon」係指天然存在之cereblon蛋白或其部分以及包含與天然存在之cereblon蛋白或其部分至少80%、85%、90%、95%、96%、97%、98%或99%同源或序列一致的多肽，其中序列可例如在本文所描述之cereblon結合化合物之存在下結合cereblon相關蛋白。 如本文中所使用，「cereblon相關蛋白」係指例如在cereblon結合化合物之存在下充當例如可與cereblon結合及/或與cereblon相關聯的cereblon之基體的蛋白(或其部分)。參看例如Gandhi等人,2014, Br. J. Haematol. 164(6): 811-821。 在一特定實施例中，用於本文所描述之CAR中之cereblon相關蛋白為Aiolos。Aiolos亦稱為「IKAROS家族鋅指3」、「鋅指蛋白，子族1A，3」及ZNFN1A3。在Genbank Gene ID: 22806下提供編碼Aiolos之例示性核酸。例如在Uniprot ID: Q9UKT9-1下提供例示性Aiolos胺基酸序列。熟習此項技術者將易於瞭解如何使用重組工程改造來製造並使用含Aiolos之多肽。如本文中所使用，術語「Aiolos」係指天然存在之Aiolos蛋白或其部分以及包含與天然存在之Aiolos蛋白或其部分至少80%、85%、90%、95%、96%、97%、98%或99%同源或序列一致的多肽。 在另一特定實施例中，用於本文所描述之CAR中之cereblon相關蛋白為Ikaros。Ikaros亦稱為「IKAROS家族鋅指1」、IKZF1、IK1、LYF1、LyF-1、CVID13、PPP1R92、PRO0758、ZNFN1A1及HS.54452。例如在Genbank Gene ID: 10320下提供編碼Ikaros之例示性核酸。例如在Uniprot ID: Q03267-1下提供例示性Ikaros胺基酸序列。熟習此項技術者將易於瞭解如何使用重組工程改造來製造並使用含Ikaros之多肽。如本文中所使用，術語「Ikaros」係指天然存在之Ikaros蛋白或部分其以及包含與天然存在之Ikaros蛋白或其部分至少80%、85%、90%、95%、96%、97%、98%或99%同源或序列一致的多肽。抗原結合域 本文所提供之CAR之抗原結合域可為與抗原結合的任何多肽域、基元或序列。 在某些實施例中，本文所描述之CAR之抗原結合域為受體之抗原結合部分。在一特定實施例中，本文所描述之CAR之抗原結合域為用於由腫瘤細胞產生之配位體的受體。 在某些實施例中，本文所描述之CAR之抗原結合域為抗體之抗原結合部分。在一特定實施例中，本文所描述之CAR之抗原結合域為抗體、抗體鏈、單鏈抗體或其抗原結合部分、Fc域、糖磷脂醯肌醇錨定域或scFv抗體片段。 在某些實施例中，本文所描述之CAR之抗原結合域為基於肽之巨分子抗原結合劑，例如噬菌體呈現蛋白。 在某些實施例中，藉由本文所描述之CAR之抗原結合域結合的抗原受限於與主要組織相容性複合體(MHC)相關聯之抗原遞呈。在某些實施例中，藉由本文所描述之CAR之抗原結合域結合的抗原為MHC不受限的。 藉由本文所描述之CAR之抗原結合域所結合/識別的抗原可為任何所關注抗原。在一特定實施例中，該抗原為在細胞(例如，腫瘤細胞，諸如實體腫瘤細胞或血癌腫瘤細胞)之表面上表現的抗原。 在一特定實施例中，藉由本文所描述之CAR之抗原結合域所結合/識別的抗原為腫瘤細胞上之抗原，例如該抗原為TSA或TAA。可藉由本文所描述之CAR識別(亦即，藉由CAR之抗原結合域結合)之例示性腫瘤細胞抗原包括(但不限於)：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及波形蛋白。 在另一特定實施例中，藉由本文所描述之CAR之抗原結合域所結合/識別的抗原為在以下之腫瘤細胞上表現或與以下之腫瘤細胞相關聯之抗原：淋巴瘤/白血病、肺癌、乳癌、前列腺癌、腎上腺皮質癌瘤、甲狀腺癌瘤、鼻咽癌瘤、黑素瘤(例如，惡性黑色素瘤)、皮膚癌瘤、結腸直腸癌、硬纖維腫瘤、促結締組織增生性小圓細胞腫瘤、內分泌腫瘤、尤文氏肉瘤、周邊原始神經外胚層瘤、固體生殖細胞腫瘤、肝母細胞瘤、神經母細胞瘤、非橫紋肌肉瘤軟組織肉瘤、骨肉瘤、視網膜母細胞瘤、橫紋肌肉瘤、威爾姆斯腫瘤、神經膠母細胞瘤、黏液瘤、纖維瘤、脂肪瘤或類似腫瘤。 在另一特定實施例中，藉由本文所描述之CAR之抗原結合域所結合/識別的抗原為在以下之腫瘤細胞上表現或與以下之腫瘤細胞相關聯之抗原：慢性淋巴球性白血病(小淋巴球性淋巴瘤)、B細胞前淋巴球性白血病、淋巴漿細胞性淋巴瘤、瓦爾登斯特倫巨球蛋白血症、脾邊緣區淋巴瘤、漿細胞骨髓瘤、漿細胞瘤、結外邊緣區B細胞淋巴瘤、MALT淋巴瘤、結邊緣區B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特氏淋巴瘤、T淋巴球前淋巴球性白血病、T淋巴球大顆粒淋巴球性白血病、侵襲性NK細胞白血病、成人T淋巴球白血病/淋巴瘤、結外NK/T淋巴球淋巴瘤、鼻型、腸病型T淋巴球淋巴瘤、肝脾T淋巴球淋巴瘤、母細胞性NK細胞淋巴瘤、蕈樣黴菌病、塞紮萊症候群、原發性皮膚多形性大細胞淋巴瘤、淋巴瘤樣丘疹病、血管免疫母細胞T淋巴球淋巴瘤、周邊T淋巴球淋巴瘤(未指定)、多形性大細胞淋巴瘤、霍奇金淋巴瘤或非霍奇金淋巴瘤。 在另一特定實施例中，藉由本文所描述之CAR之抗原結合域所結合/識別的抗原為非腫瘤相關抗原或非腫瘤特異性抗原。在某些實施例中，抗原係關於腫瘤之態樣，例如，腫瘤環境。舉例而言，腫瘤可在該腫瘤周圍之組織中誘導發炎性狀態，且可將促進血管生成之血管生成生長因子、介白素及/或細胞介素釋放至腫瘤中及腫瘤之周邊處。因此，在某些實施例中，抗原為生長因子、細胞介素或介白素(例如，與血管生成或血小管生成相關聯之生長因子、細胞介素或介白素)。此類生長因子、細胞介素及介白素可包括(但不限於)血管內皮生長因子(VEGF)、鹼性纖維母細胞生長因子(bFGF)、血小板衍生生長因子(PDGF)、肝細胞生長因子(HGF)、胰島素類生長因子(IGF)及介白素-8 (IL-8)。 在另一特定實施例中，藉由本文所描述之CAR之抗原結合域所結合/識別的抗原為回應於由腫瘤造成之局部損傷的由正常組織釋放之損傷相關分子模式分子(DAMP；亦稱為報警素)。可與本文所描述之CAR之抗原結合域結合的例示性DAMP包括(但不限於)熱休克蛋白、染色體相關蛋白高遷移率族匣1 (HMGB1)、S100A8 (MRP8，鈣粒蛋白A)、S100A9 (MRP14，鈣粒蛋白B)、血清澱粉樣蛋白A (SAA)、脫氧核糖核酸、腺苷三磷酸、尿酸及硫酸肝素。跨膜域 本文所描述之CAR之跨膜域可包含充當跨膜域之此項技術中已知的任何分子，例如熟習此項技術者已知的CAR背景中的官能。本文所描述之CAR之跨膜域可獲自或衍生自任何跨膜蛋白之跨膜域，且可包括此跨膜域之全部或一部分。 在一特定實施例中，本文所描述之CAR之第一多肽及/或第二多肽的跨膜域獲自或衍生自T細胞受體，例如，本文所描述之CAR之第一多肽及/或第二多肽的跨膜域獲自或衍生自T細胞受體之α鏈、T細胞受體之β鏈、T細胞受體之ζ鏈。 在特定實施例中，本文所描述之CAR之第一多肽及/或第二多肽的跨膜域獲自或衍生自CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154、細胞介素受體、介白素受體或生長因子受體。信號傳導域 本文所描述之CAR之原代細胞信號傳導域可包含充當細胞信號傳導域之此項技術中已知的任何分子，例如熟習此項技術者已知的CAR背景中之官能。在一特定實施例中，本文所描述之CAR之細胞信號傳導域包含原代T細胞信號傳導域。 在一特定實施例中，本文所描述之CAR之原代細胞信號傳導域為ZAP-70或其信號轉導變體或包含ZAP-70或其信號轉導變體。 在另一特定實施例中，本文所描述之CAR之原代細胞信號傳導域為ITAM或包含ITAM。在一特定實施例中，該ITAM為FcRγ、FcRβ、CD3ζ、CD3γ、CD3δ、CD3ε、CD5、CD22、20 CD79a、CD79b、CD278 (ICOS)、FcERI、CD66d、DAP10或DAP12之ITAM。共刺激域 在某些實施例中，本文所描述之CAR之第一多肽及/或第二多肽包含共刺激域。本文所描述之CAR之共刺激域可包含充當共刺激域之此項技術中已知任何分子，例如熟習此項技術者已知CAR背景中之官能。 在一特定實施例中，本文所描述之CAR之第一多肽及/或第二多肽的共刺激域獲自或衍生自共刺激CD27多肽序列、共刺激CD28多肽序列、共刺激OX40 (CD134)多肽序列、共刺激4-1BB (CD137)多肽序列或共刺激可誘導T細胞共刺激(ICOS)多肽序列。 在另一特定實施例中，本文所描述之CAR之第一多肽及/或第二多肽的共刺激域為以下或包含以下：CD28、4-1BB (CD137)、OX40、活化NK細胞受體、BTLA、Toll配位體受體、CD2、CD7、CD27、CD30、CD40、CDS、ICAM-L LFA-1 (CD11a/CD18)、B7-H3、CDS、ICAM-1、ICOS (CD278)、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、NKG2C、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、DAP10、DAP12、CD83之配位體、MHC I類分子、TNF受體蛋白、免疫球蛋白類蛋白、細胞介素受體、整合素或信號傳導淋巴球性活化分子。其他修飾 在某些實施例中，本文所描述之CAR之第一多肽及/或第二多肽進一步包含回應於調節劑(亦即，除cereblon結合化合物以外的試劑)之二聚域。 在某些實施例中，本文所描述之CAR之第一多肽及/或第二多肽進一步包含T細胞存活基元。T細胞存活基元可為在藉由抗原刺激之後有助於T淋巴球存活之任何多肽序列或基元。在某些實施例中，T細胞存活基元為以下或衍生自以下：CD3、CD28、IL-7受體(IL-7R)之胞內信號傳導域、IL-12受體之胞內信號傳導域、IL-15受體之胞內信號傳導域、IL-21受體之胞內信號傳導域或轉型生長因子ß (TGFß)受體之胞內信號傳導域。4.1.2. CAR 多肽修飾 在某些實施例中，本文所提供之CAR之第一多肽及/或第二多肽藉由例如醯化、醯胺化、糖基化、甲基化、磷酸化、硫酸化、蘇素化及/或泛素化(或其他蛋白修飾)來修飾。 在某些實施例中，本文所提供之CAR之第一多肽及/或第二多肽標記有能夠提供可偵測信號之標記，例如放射性同位素或螢光化合物。 在某些實施例中，本文所提供之CAR之第一多肽及/或第二多肽的一或多個側鏈衍生，例如，離胺醯基及胺基端殘基用丁二酸或其他羧酸酐衍生化，或用例如醯亞胺酯(諸如吡啶甲醯亞胺酸甲酯)、磷酸吡哆醛、吡哆醛、氯硼氫化物、三硝基苯磺酸、O-甲基異脲、2,4戊二酮及與乙醛酸鹽轉胺酶催化反應衍生化。在某些實施例中，羧基側基、天冬胺醯基或麩胺醯基可藉由與碳化二亞胺 (R—N=C=N—R') (諸如1-環己基-3-(2-嗎啉基-(4-乙基)碳化二亞胺或1-乙基-3-(4-氮鎓-4,4-二甲基戊基)碳化二亞胺)反應而選擇性地經修飾。4.1.3. 核酸 本文提供對本文所描述之CAR進行編碼之核酸，亦即，對本文所描述之CAR的第一多肽進行編碼之核酸及對本文所描述之CAR的第二多肽進行編碼之核酸。在某些實施例中，本文所描述之CAR的第一多肽由第一核酸(聚核苷酸)編碼且本文所描述之CAR的第二多肽由第二核酸(聚核苷酸)編碼。在一特定實施例中，本文提供對本文所描述之CAR的第一多肽及第二多肽兩者進行編碼之核酸(聚核苷酸)。 適用於產生本文所描述之CAR之核酸包括DNA、RNA及核酸類似物。核酸類似物可在鹼基部分、糖部分或磷酸主鏈處經修飾，且可包括脫氧尿苷取代脫氧胸苷、5-甲基-2'-脫氧胞苷或5-溴-2'-脫氧胞苷取代脫氧胞苷。糖部分之修飾可包括核糖之2'羥基的修飾以形成2'-O-甲基糖或2'-O-烯丙基糖。脫氧核苷磷酸主鏈可經修飾以產生嗎啉基核酸，其中每一鹼基部分連接至六員嗎啉基環或肽核酸，其中脫氧磷酸主鏈經偽肽主鏈置換且保留四種鹼基。參見例如Summerton及Weller (1997) Antisense Nucleic Acid Drug Dev. 7:187-195；及Hyrup等人 (1996) Bioorgan. Med. Chain. 4:5-23。另外，脫氧磷酸主鏈可經例如硫代磷酸酯或二硫代磷酸酯主鏈、亞磷醯胺或烷基磷酸三酯主鏈置換。 在某些實施例中，本文所描述之CAR多肽編碼核酸包含於核酸載體內。舉例而言，所關注細胞(例如，T淋巴球)可使用含有對本文所描述之CAR的第一多肽及/或第二多肽進行編碼之核酸(聚核苷酸)的合成載體、慢病毒或反轉錄病毒載體、自主複寫質粒、病毒(例如，反轉錄病毒、慢病毒、腺病毒或疱疹病毒)或其類似者轉型。在一特定實施例中，包含本文所描述之CAR的第一多肽及/或第二多肽之載體為反轉錄病毒載體。在另一特定實施例中，包含本文所描述之CAR的第一多肽及/或第二多肽之載體為慢病毒載體。適用於細胞(例如，T淋巴球)之轉型的慢病毒載體包括(但不限於)美國專利第5,994,136號、第6,165,782號、第6,428,953號、第7,083,981號及第7,250,299號中所描述之慢病毒載體。適用於細胞(例如，T淋巴球)之轉型的HIV載體包括(但不限於)美國專利第5,665,577號中所描述之載體。 在某些實施例中，本文所描述之CAR多肽編碼核酸可操作地連接至啟動子。在一特定實施例中，該啟動子為T細胞特異性啟動子、自然殺手(NK)細胞特異性啟動子、作用於T細胞或NK細胞內之誘導型啟動子或組成型啟動子。4.1.4. 細胞 本文所提供之CAR可在CAR表現對細胞有效之該等細胞中表現，亦即經工程改造以包含本文所提供之CAR編碼核酸之細胞，使得在細胞中表現核酸之後，細胞表現本文所描述之CAR。舉例而言，本文所描述之CAR可在T淋巴球或自然殺手細胞中表現。表現本文所描述之CAR的本文所提供之細胞被稱為「CAR細胞」。 在某些實施例中，本文提供經修飾以表現CAR之細胞(例如，T淋巴球或自然殺手細胞)，該CAR包含：(i)第一多肽，其包含能夠結合cereblon結合化合物之cereblon或其官能性部分；及(ii)第二多肽，其包含能夠結合cereblon結合化合物之cereblon相關蛋白(例如，Aiolos或Ikaros)或其官能性部分。在一特定實施例中，第一多肽進一步包含抗原結合域及跨膜域(及視情況，共刺激域)。在一特定實施例中，第二多肽進一步包含跨膜域及原代細胞信號傳導域(及視情況，共刺激域)。 在一特定實施例中，本文所提供之CAR在T淋巴球中表現。T淋巴球可為原初T淋巴球或MHC限制性T淋巴球。在某些實施例中，T淋巴球為腫瘤浸潤性淋巴球(TIL)。在某些實施例中，T淋巴球自腫瘤生物檢體分離或由自腫瘤生物檢體分離之T淋巴球擴增。在某些其他實施例中，T淋巴球已自周邊血液、臍帶血液或淋巴分離或由自周邊血液、臍帶血液或淋巴擴增之T淋巴球擴增。 在一特定實施例中，經工程改造以包含/表現本文所描述之CAR的細胞(例如，T淋巴球)對作為本文所描述之治療方法之部分而待投與之該等細胞(例如，T淋巴球)的個體而言為自體的。在其他實施例中，經工程改造以包含/表現本文所描述之CAR的細胞(例如，T淋巴球)對待投與之該等細胞(例如，T淋巴球)的個體而言為同種異體的。在同種異體細胞(例如，T淋巴球)用於製備CAR細胞之情況下，較佳的為選擇將降低個體中之移植物抗宿主病(GVHD)之可能性的細胞(例如，T淋巴球)。舉例而言，在某些實施例中，病毒特異性T淋巴球經選擇以用於製備CAR T淋巴球；將期望此類淋巴球具有與任何受體抗原結合且因此藉由任何受體抗原變得活化的極大降低的天然能力。在某些實施例中，經受體介導之同種異體細胞(例如，T淋巴球)的排斥反應可藉由向宿主共投與一或多種免疫抑制劑來減少，該等一或多種免疫抑制劑例如環孢黴素(cyclosporine)、他克莫司(tacrolimus)、西羅莫司(sirolimus)、環磷醯胺(cyclophosphamide)或其類似物。 在一個實施例中，T淋巴球獲自個體，接著視需要擴增，且接著用對本文所描述之CAR之第一多肽進行編碼的第一載體及對本文所描述之CAR之第二多肽進行編碼的第二載體轉型，且接著視需要擴增。可使用對載體中之每一者而言獨特的可選標記來選擇雙轉型體。 在另一實施例中，T淋巴球獲自個體，接著視需要擴增，且接著用對本文所描述之CAR之第一多肽及第二多肽進行編碼的載體轉型，且接著視需要擴增。可使用可選標記來獲得含有該載體之細胞。 在某些實施例中，除人工共刺激多肽(在使用共刺激多肽之實施例中)以外或除第一多肽及第二多肽(在CAR細胞包含使抗原結合信號傳導與共刺激信號傳導分離之多肽的實施例中)以外，用於產生本文所提供之CAR細胞的T淋巴球包含天然TCR蛋白，例如能夠形成天然TCR複合體的TCR-α及TCR-β。在某些其他實施例中，對T淋巴球中之TCR-α及TCR-β進行編碼的原代基因中之任一者或兩者經修飾為非官能性的，例如缺失部分或全部或插入突變。 在某些實施例中，本文所描述之CAR之信號傳導域可用於促進包含/表現CAR之細胞(例如，T淋巴球)之增殖及擴增。舉例而言，未經修飾之T淋巴球及包含多肽(包含CD3ζ信號傳導域及CD28共刺激域)的T淋巴球可使用針對CD3及CD28之抗體(例如，連接至珠粒之抗體)而擴增；參看例如美國專利第5,948,893號、第6,534,055號、第6,352,694號、第6,692,964號、第6,887,466號及第6,905,681號。類似地，針對信號傳導基元之抗體可用於刺激包含本文所描述之CAR的細胞(例如，T淋巴球)之增殖。 在某些實施例中，本文所描述之CAR細胞包含能夠在需要時殺滅基本上所有CAR細胞的「自殺基因」或「安全切換」。舉例而言，在某些實施例中，本文所描述之CAR細胞包含HSV胸苷激酶基因(HSV-TK)，其在與更昔洛韋(gancyclovir)接觸後造成細胞死亡。在另一實施例中，CAR細胞包含誘導型凋亡蛋白酶，例如誘導型凋亡蛋白酶9 (icaspase9)、例如允許使用特異性小分子藥物二聚化的凋亡蛋白酶9與人類FK506結合蛋白之間的融合蛋白。參看Straathof等人, Blood 105(11):4247-4254 (2005)。 在某些實施例中，本文所提供之CAR細胞進一步包含人工細胞死亡多肽，該人工細胞死亡多肽包含細胞凋亡誘導域及二聚域，其中該人工細胞死亡多肽可使用二聚劑二聚化，且其中當人工細胞死亡多肽經二聚化時，該多肽在該細胞中產生細胞凋亡誘導信號。在一特定實施例中，該二聚劑為雷帕黴素或雷帕黴素之類似物(雷帕黴素類似物)。在另一特定實施例中，該二聚劑為AP1903 (rimiducid)。在另一特定實施例中，該二聚劑不為cereblon結合化合物。在一特定實施例中，該二聚域為FK結合域或其類似物。在另一特定實施例中，該二聚劑為與該FK結合域結合之抗體。4.1.5. 使用方法 本文所提供之CAR細胞(例如，經修飾以包含/表現本文所描述之CAR的T淋巴球)可用於治療具有需要由該等細胞靶向(例如，殺死)的一或多種類型之細胞的個體。 在一特定實施例中，本文提供用於殺滅表現由本文所描述之CAR之抗原結合域結合的抗原之靶細胞的方法，其中該等方法包含：(i)使該等靶細胞與包含/表現本文所描述之CAR的細胞(例如，T細胞或NK細胞)接觸；及(ii)使該CAR表現細胞與cereblon結合化合物接觸，其中在該抗原及該cereblon結合化合物之存在下，該CAR表現細胞變得活化。在一特定實施例中，該靶細胞為癌細胞，例如血癌細胞或實體腫瘤細胞。在另一特定實施例中，該靶細胞表現一或多個以下抗原或其片段：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在另一特定實施例中，本文提供治療癌症之方法，該等方法包含：(i)向個體(例如，人類個體)投與包含/表現本文所描述之CAR (例如，包含本文所描述之CAR編碼核酸或表現本文所描述之CAR)之本文所描述之CAR細胞(例如，T細胞或NK細胞)群體，其中該CAR包含對癌抗原(例如，TSA或TAA)具有特異性之抗原結合域；及(ii)向該個體投與包含cereblon結合化合物之組合物。在一特定實施例中，首先向個體投與該細胞群體，接著在投與細胞群體後之特定時段處(例如，在投與細胞群體後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，投與包含cereblon結合化合物之組合物。在一特定實施例中，由該CAR結合之該抗原為：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在一特定實施例中，根據本文所描述之治療癌症之方法而向個體投與之cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 可根據本文所描述之治療方法治療之癌症的非限制性清單包括：淋巴瘤、白血病、肺癌、乳癌、前列腺癌、腎上腺皮質癌瘤、甲狀腺癌瘤、鼻咽癌瘤、黑素瘤、皮膚癌瘤、結腸直腸癌、硬纖維腫瘤、促結締組織增生性小圓細胞腫瘤、內分泌腫瘤、尤文氏肉瘤、周邊原始神經外胚層瘤、固體生殖細胞腫瘤、肝母細胞瘤、神經母細胞瘤、非橫紋肌肉瘤軟組織肉瘤、骨肉瘤、視網膜母細胞瘤、橫紋肌肉瘤、威爾姆斯腫瘤、神經膠瘤、神經膠母細胞瘤、黏液瘤、纖維瘤及脂肪瘤。例示性淋巴瘤及白血病包括(但不限於)：慢性淋巴球性白血病(小淋巴球性淋巴瘤)、B細胞前淋巴球性白血病、淋巴漿細胞性淋巴瘤、瓦爾登斯特倫巨球蛋白血症、脾邊緣區淋巴瘤、漿細胞骨髓瘤、漿細胞瘤、結外邊緣區B細胞淋巴瘤、MALT淋巴瘤、結邊緣區B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特氏淋巴瘤、T淋巴球前淋巴球性白血病、T淋巴球大顆粒淋巴球性白血病、侵襲性NK細胞白血病、成人T淋巴球白血病/淋巴瘤、結外NK/T淋巴球淋巴瘤、鼻型、腸病型T淋巴球淋巴瘤、肝脾T淋巴球淋巴瘤、母細胞性NK細胞淋巴瘤、蕈樣黴菌病、塞紮萊症候群、原發性皮膚多形性大細胞淋巴瘤、淋巴瘤樣丘疹病、血管免疫母細胞T淋巴球淋巴瘤、周邊T淋巴球淋巴瘤(未指定)、多形性大細胞淋巴瘤、霍奇金淋巴瘤或非霍奇金淋巴瘤。 本文所描述之CAR細胞在治療疾病或病症中(例如，在治療患有癌症之個體中)之功效可藉由一般技術者已知之特定針對於特定疾病或病症的一或多個標準來評定，以指示疾病或病症之進展。大體而言，當該等準則中之一或多者可偵測地(例如，顯著地)自疾病狀態值或範圍移動至正常值或範圍或朝向正常值或範圍時，向患有疾病/病症(例如，癌症)之個體投與CAR細胞(例如，CAR T淋巴球)係有效的。 本文所描述之CAR細胞可以任何醫藥學上可接受之溶液調配，較佳為適用於遞送活細胞之溶液，例如生理鹽水溶液(諸如林格氏溶液(Ringer's solution))、明膠、碳水化合物(例如，乳糖、直鏈澱粉、澱粉或其類似者)、脂肪酸酯、羥甲基纖維素、聚乙烯吡咯烷(polyvinyl pyrolidine)等。此類製劑較佳地在添加CAR細胞之前進行除菌，且可與諸如潤滑劑、防腐劑、穩定劑、乳化劑、鹽的輔助劑混合，以影響滲透壓、緩衝及著色。適用於調配本文所描述之CAR細胞的醫藥載劑為此項技術中已知的且描述於例如WO 96/05309中。 在某些實施例中，將本文所描述之CAR細胞(例如，CAR T淋巴球)調配成單個劑量，其中該單個劑包含至少、至多或約1×104 、5×104 、1×105 、5×105 、1×106 、5×106 、1×107 、5×107 、1×108 、5×108 、1×109 、5×109 、1×1010 、5×1010 或1×1011 個CAR細胞。 在某些實施例中，本文所描述之CAR細胞(例如，CAR T淋巴球)經調配以供靜脈內、動脈內、非經腸、肌內、皮下、鞘內或眼內投與，或在特定器官或組織內投與。Cereblon 結合化合物 如本文中所使用，術語「cereblon結合化合物」係指能夠結合cereblon (或其官能性部分)及能夠結合cereblon相關蛋白(或其官能性部分) (例如，Aiolos (或其官能性部分)或Ikaros (或其官能性部分))的分子(例如，小分子或蛋白/多肽(例如，抗體))。在一特定實施例中，cereblon結合化合物能夠結合cereblon (或其官能性部分)及Aiolos (或其官能性部分)兩者，導致cereblon (或其官能性部分)與Aiolos (或其官能性部分)之間的關聯，例如異質二聚體之形成。在另一特定實施例中，cereblon結合化合物能夠結合cereblon (或其官能性部分)及Ikaros (或其官能性部分)兩者，導致cereblon (或其官能性部分)與Ikaros (或其官能性部分)之間的關聯，例如異質二聚體之形成。 在一特定實施例中，根據本文所描述之方法使用之cereblon結合化合物為泊利度胺(4-胺基-2-[(3RS)-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，根據本文所描述之方法使用之cereblon結合化合物為沙立度胺((RS)-2-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)。在另一特定實施例中，根據本文所描述之方法使用之cereblon結合化合物為來那度胺(3-(4-胺基-1-側氧基-1,3-二氫-2H-異吲哚-2-基)哌啶-2,6-二酮)。在另一特定實施例中，根據本文所描述之方法使用之cereblon結合化合物為3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮。在另一特定實施例中，根據本文所描述之方法使用之cereblon結合化合物為3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。參看，例如針對與此等化合物相關的揭示內容的美國專利申請公開案第2014/0162282號，其以全文引用的方式併入本文中。 根據本文所描述之方法使用之cereblon結合化合物或對映異構體或其對映異構體之混合物或醫藥學上可接受之鹽、溶劑、水合物、共晶體、籠形物或其多晶型物可作為單次劑量(諸如(例如)單次快速注射或口服錠劑或丸劑)或隨時間推移(諸如(例如)隨時間推移連續輸注或隨時間推移分開的快速給藥)遞送。 根據本文所描述之方法使用之cereblon結合化合物可經調配用於靜脈內、動脈內、非經腸、肌內、皮下、鞘內或眼內投與，或在特定器官或組織內投與。4.2. 人工細胞死亡多肽 4.2.1. 細胞死亡多肽構建體 本文亦提供可二聚化人工細胞死亡受體，其包含第一多肽(包含cereblon或其官能性部分)及第二多肽(包含cereblon相關蛋白或其官能性部分)，當在細胞(例如，T淋巴球或NK細胞)中表現時，該等受體可在cereblon結合化合物之存在下導致細胞之死亡。Cereblon、cereblon相關蛋白及cereblon結合化合物詳細描述於以上章節4.1中。 在一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分)；及(b)第二多肽，其包含細胞凋亡誘導域(或其官能性部分)及Aiolos (或其官能性部分)，其中該cereblon (或其官能性部分)及該Aiolos (或其官能性部分)兩者均能夠結合cereblon結合化合物，且其中該第一多肽及該第二多肽在該cereblon結合化合物之存在下二聚以產生細胞凋亡誘導信號。在一特定實施例中，該cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon(或其官能性部分))；及(b)第二多肽，其包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分)。在一特定實施例中，該第二多肽包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分))。在一特定實施例中，該cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含胞外域(包含cereblon (或其官能性部分))、跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分))；及(b)第二多肽，其包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分)。在另一特定實施例中，該第二多肽包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分))。在另一特定實施例中，該第二多肽包含跨膜蛋白，該跨膜蛋白包含胞外域(包含cereblon相關蛋白(或其官能性部分))、跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分))。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分)；及(b)第二多肽，其包含跨膜蛋白，該跨膜蛋白包含跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分)及cereblon相關蛋白(或其官能性部分))。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 在另一特定實施例中，本文提供一種可二聚化人工細胞死亡受體，其包含：(a)第一多肽，其包含跨膜蛋白，該跨膜蛋白包含細胞凋亡誘導域(或其官能性部分)及cereblon (或其官能性部分)；及(b)第二多肽，其包含跨膜蛋白，該跨膜蛋白包含胞外域(包含cereblon相關蛋白(或其官能性部分))、跨膜域及胞內域(包含細胞凋亡誘導域(或其官能性部分))。在一特定實施例中，cereblon相關蛋白為Aiolos或Ikaros。 細胞死亡多肽之細胞凋亡誘導域可為例如任何蛋白或其部分，該蛋白或其部分在二聚化時啟動細胞凋亡誘導信號。在某些實施例中，細胞凋亡誘導域為均二聚之任何凋亡蛋白酶。在一特定實施例中，細胞凋亡誘導域為凋亡蛋白酶或包含該凋亡蛋白酶，例如凋亡蛋白酶9、凋亡蛋白酶8或凋亡蛋白酶3 (例如，人體凋亡蛋白酶9、人體凋亡蛋白酶8或人體凋亡蛋白酶3)。包括人體凋亡蛋白酶9、人體凋亡蛋白酶8及人體凋亡蛋白酶3之人體凋亡蛋白酶之胺基酸序列為此項技術中所熟知的。舉例而言，人體凋亡蛋白酶3經指定為NCBI Gene ID: 836；人體凋亡蛋白酶8經指定為NCBI Gene ID: 841；且人體凋亡蛋白酶9經指定為NCBI Gene ID: 842。在某些實施例中，為凋亡蛋白酶域或包含該凋亡蛋白酶域之胞內域及胞外域藉由CD8α莖或CD8β莖接合，其之至少部分可充當跨膜域。4.2.2. 核酸 本文提供對本文所描述之可二聚化人工細胞死亡受體進行編碼的核酸，亦即對本文所描述之可二聚化人工細胞死亡受體的第一多肽進行編碼之核酸及對可二聚化人工細胞死亡受體的第二多肽進行編碼之核酸。在某些實施例中，本文所描述之可二聚化人工細胞死亡受體之第一多肽由第一核酸(聚核苷酸)編碼且本文所描述之可二聚化人工細胞死亡受體之第二多肽由第二核酸(聚核苷酸)編碼。在一特定實施例中，本文提供對本文所描述之可二聚化人工細胞死亡受體之第一多肽及第二多肽兩者進行編碼的核酸(聚核苷酸)。 適用於製備本文所描述之人工細胞死亡受體之核酸包括DNA、RNA及核酸類似物。核酸類似物可在鹼基部分、糖部分或磷酸主鏈處經修飾，且可包括脫氧尿苷取代脫氧胸苷、5-甲基-2'-脫氧胞苷或5-溴-2'-脫氧胞苷取代脫氧胞苷。糖部分之修飾可包括核糖之2'羥基的修飾以形成2'-O-甲基糖或2'-O-烯丙基糖。脫氧核苷磷酸主鏈可經修飾以產生嗎啉基核酸，其中每一鹼基部分連接至六員嗎啉基環或肽核酸，其中脫氧磷酸主鏈經偽肽主鏈置換且保留四種鹼基。參見例如Summerton及Weller (1997) Antisense Nucleic Acid Drug Dev. 7:187-195；及Hyrup等人 (1996) Bioorgan. Med. Chain. 4:5-23。另外，脫氧磷酸主鏈可經例如硫代磷酸酯或二硫代磷酸酯主鏈、亞磷醯胺或烷基磷酸三酯主鏈置換。 在某些實施例中，本文所描述之人工細胞死亡受體編碼核酸包含於核酸載體內。舉例而言，所關注細胞(例如，T淋巴球)可使用含有對本文所描述之人工細胞死亡受體之第一多肽及/或第二多肽進行編碼之核酸(聚核苷酸)的合成載體、慢病毒或反轉錄病毒載體、自主複寫質粒、病毒(例如，反轉錄病毒、慢病毒腺病毒或疱疹病毒)或其類似者轉型。在一特定實施例中，包含本文所描述之人工細胞死亡受體之第一多肽及/或第二多肽的載體為反轉錄病毒載體。在另一特定實施例中，包含本文所描述之人工細胞死亡受體之第一多肽及/或第二多肽的載體為慢病毒載體。適用於細胞(例如，T淋巴球)之轉型的慢病毒載體包括(但不限於)美國專利第5,994,136號、第6,165,782號、第6,428,953號、第7,083,981號及第7,250,299號中所描述之慢病毒載體。適用於細胞(例如，T淋巴球)之轉型的HIV載體包括(但不限於)美國專利第5,665,577號中所描述之載體。 在某些實施例中，本文所描述之人工細胞死亡受體編碼核酸可操作地連接至啟動子。在一特定實施例中，該啟動子為T細胞特異性啟動子、自然殺手(NK)細胞特異性啟動子、作用於T細胞或NK細胞內之誘導型啟動子或組成型啟動子。4.2.3. 細胞 本文所提供之人工細胞死亡受體可在表現對細胞有用之該等細胞中表現，亦即經工程改造以包含本文所提供之人工細胞死亡受體編碼核酸的細胞，使得在細胞中表現核酸之後，該細胞表現本文所描述之人工細胞死亡受體。舉例而言，本文所描述之人工細胞死亡受體可在T淋巴球或自然殺手細胞中表現。表現本文所描述之人工細胞死亡受體的本文所提供之細胞被稱為「細胞死亡受體細胞」。 在一特定實施例中，本文所提供之人工細胞死亡受體在T淋巴球中表現。T淋巴球可為原初T淋巴球或MHC限制性T淋巴球。在某些實施例中，T淋巴球為腫瘤浸潤性淋巴球(TIL)。在某些實施例中，T淋巴球自腫瘤生物檢體分離或由自腫瘤生物檢體分離之T淋巴球擴增。在某些其他實施例中，T淋巴球已自周邊血液、臍帶血液或淋巴分離或由自周邊血液、臍帶血液或淋巴擴增之T淋巴球擴增。 在一特定實施例中，本文所描述之細胞死亡受體細胞對作為本文所描述之治療方法之部分而待投與之該等細胞(例如，T淋巴球)的個體而言為自體的。在其他實施例中，本文所描述之細胞死亡受體細胞對待投與之該等細胞(例如，T淋巴球)的個體而言為同種異體的。在同種異體的細胞(例如，T淋巴球)用於製備包含/表現人工細胞死亡受體之細胞的情況下，較佳選擇將降低個體中之移植物抗宿主病(GVHD)之可能性的細胞(例如，T淋巴球)。參看章節4.1。 在一個實施例中，T淋巴球獲自個體，接著視需要擴增，且接著用對本文所描述之人工細胞死亡受體之第一多肽進行編碼的第一載體及對本文所描述之人工細胞死亡受體之第二多肽進行編碼的第二載體轉型，且接著視需要擴增。可使用對載體中之每一者而言獨特的可選標記來選擇雙轉型體。 在另一實施例中，T淋巴球獲自個體，接著視需要擴增，且接著用對本文所描述之人工細胞死亡受體之第一多肽及第二多肽進行編碼的載體轉型，且接著視需要擴增。可使用可選標記來獲得含有該載體之細胞。 在某些實施例中，除人工共刺激多肽(在使用共刺激多肽之實施例中)以外或除第一多肽及第二多肽(在細胞包含使抗原結合信號傳導及共刺激信號傳導分離之多肽的實施例中)以外，用於產生本文所提供之細胞死亡受體細胞的T淋巴球包含天然TCR蛋白，例如能夠形成天然TCR複合體之TCR-α及TCR-β。在某些其他實施例中，對T淋巴球中之TCR-α及TCR-β進行編碼的原代基因中之任一者或兩者經修飾為非官能性的，例如缺失部分或全部或插入突變。 本文所提供之細胞死亡受體細胞(例如，包含本文所描述之可二聚化人工細胞死亡受體編碼核酸或表現本文所描述之可二聚化人工細胞死亡受體(亦即，表現本文所描述之可二聚化人工細胞死亡受體之第一多肽及第二多肽)的T細胞或NK細胞)可在與cereblon結合化合物接觸時(例如，在與泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮接觸時)經誘導以經受細胞凋亡。 本文所提供之細胞死亡受體細胞可進一步經工程改造以表現CAR，例如包含腫瘤特異性抗原結合域之CAR。舉例而言，該等CAR可選自第一代CAR (其中僅信號傳導域為CD3ζ)、第二代CAR (其包含來自CD3ζ之信號傳導域及來自CD28之共刺激域)及第三代CAR (其包含來自CD3ζ之信號傳導域及來自CD28之共刺激域及諸如4-1BB的另一蛋白)。在一特定實施例中，本文所提供之細胞死亡受體細胞之CAR包含兩個或多於兩個胞外抗原靶向域。在另一特定實施例中，本文所提供之細胞死亡受體細胞之該CAR包含與為T細胞活性之負調節劑的介白素結合的胞外域，及來自為T細胞活性之正調節劑的介白素受體的胞內域。在另一特定實施例中，藉由使細胞與cereblon結合化合物(例如，泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮)接觸而在包含人工細胞死亡受體及CAR的細胞中誘導細胞凋亡。4.2.4. 使用方法 包含本文所提供之人工細胞死亡受體及CAR之本文所提供之細胞(例如，T淋巴球)可用於治療具有需要由本文所描述之該等細胞靶向的一或多種類型之細胞(例如，待殺死的一或多種類型之細胞)的個體，其中細胞死亡受體細胞之活性可藉由投與cereblon結合化合物來控制。特定言之，細胞死亡受體細胞由於其CAR組分可用於治療，且由於其細胞死亡受體組分可在需要時被殺死，其中該殺滅藉由使細胞死亡受體細胞與cereblon結合化合物接觸來完成。 在一特定實施例中，本文提供一種用於控制靶細胞之殺滅的方法，其中該方法包含：(i)使該等靶細胞與包含本文所提供之人工細胞死亡受體及CAR的細胞死亡受體細胞(例如，T細胞或NK細胞)接觸且在允許時，(ii)使該細胞死亡受體細胞與cereblon結合化合物接觸，其中在該cereblon結合化合物之存在下，殺死細胞死亡受體細胞，例如細胞死亡受體細胞經受細胞凋亡。在一特定實施例中，該靶細胞為癌細胞，例如血癌細胞或實體腫瘤細胞。在另一特定實施例中，該靶細胞表現一或多個以下抗原或其片段：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在另一特定實施例中，本文提供一種治療癌症之方法，其中該方法包含：(i)向經診斷患有癌症之個體(例如，人類個體)投與包含本文所提供之人工細胞死亡受體及CAR的細胞死亡受體細胞(例如，T細胞或NK細胞)群體，其中該CAR包含對癌症抗原(例如，TSA或TAA)具有特異性之抗原結合域且在允許時，(ii)使該細胞死亡受體細胞與cereblon結合化合物接觸，其中在該cereblon結合化合物之存在下，細胞死亡受體細胞經受細胞凋亡。在一特定實施例中，首先向個體投與該細胞群體，接著在投與細胞群體後之特定時段處(例如，在投與細胞群體後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，投與包含cereblon結合化合物之組合物。在另一特定實施例中，首先向個體投與包含cereblon結合化合物之該組合物，接著在投與包含cereblon結合化合物之該組合物後的特定時段處(例如在投與包含cereblon結合化合物之該組合物後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)投與該細胞群體。 在一特定實施例中，由該CAR結合之該抗原為：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B-淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9 (CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23 (IgE受體)、CD28、CD30 (TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體-a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及/或波形蛋白。 在一特定實施例中，根據本文所描述之治療癌症之方法而向個體投與之cereblon結合化合物為泊利度胺、沙立度胺、來那度胺、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 可根據本文所描述之治療方法治療之癌症的非限制性清單包括：淋巴瘤、白血病、肺癌、乳癌、前列腺癌、腎上腺皮質癌瘤、甲狀腺癌瘤、鼻咽癌瘤、黑素瘤、皮膚癌瘤、結腸直腸癌、硬纖維腫瘤、促結締組織增生性小圓細胞腫瘤、內分泌腫瘤、尤文氏肉瘤、周邊原始神經外胚層瘤、固體生殖細胞腫瘤、肝母細胞瘤、神經母細胞瘤、非橫紋肌肉瘤軟組織肉瘤、骨肉瘤、視網膜母細胞瘤、橫紋肌肉瘤、威爾姆斯腫瘤、神經膠瘤、神經膠母細胞瘤、黏液瘤、纖維瘤及脂肪瘤。例示性淋巴瘤及白血病包括(但不限於)：慢性淋巴球性白血病(小淋巴球性淋巴瘤)、B細胞前淋巴球性白血病、淋巴漿細胞性淋巴瘤、瓦爾登斯特倫巨球蛋白血症、脾邊緣區淋巴瘤、漿細胞骨髓瘤、漿細胞瘤、結外邊緣區B細胞淋巴瘤、MALT淋巴瘤、結邊緣區B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特氏淋巴瘤、T淋巴球前淋巴球性白血病、T淋巴球大顆粒淋巴球性白血病、侵襲性NK細胞白血病、成人T淋巴球白血病/淋巴瘤、結外NK/T淋巴球淋巴瘤、鼻型、腸病型T淋巴球淋巴瘤、肝脾T淋巴球淋巴瘤、母細胞性NK細胞淋巴瘤、蕈樣黴菌病、塞紮萊症候群、原發性皮膚多形性大細胞淋巴瘤、淋巴瘤樣丘疹病、血管免疫母細胞T淋巴球淋巴瘤、周邊T淋巴球淋巴瘤(未指定)、多形性大細胞淋巴瘤、霍奇金淋巴瘤或非霍奇金淋巴瘤。實例 此實例描述包含嵌合抗原受體(CAR)之經修飾T淋巴球的產生及用途，其中CAR包含：第一多肽，其包含對腫瘤特異性抗原具有特異性的抗原結合域、共刺激域及cereblon；及第二多肽，其包含cereblon相關蛋白(例如，Aiolos)及基於CD3ζ免疫受體酪胺酸的活化基元(ITAM)原代細胞信號傳導域。CAR 構建體 使用標準方法製備圖1中所描繪之CAR。 構建對第一多肽、腫瘤抗原結合蛋白(例如，抗-HER2 scFv、抗PSCA scFv或抗BCMA scFv)基於cereblon(CRBN)之CAR (亦即含有抗腫瘤抗原抗體之scFv、CD28跨膜(TM)域、CD28共刺激域及CRBN之「第一多肽」)進行編碼的第一聚核苷酸。將第一聚核苷酸選殖至慢病毒載體中。 構建對第二多肽、基於Aiolos之ITAM CAR (亦即含有CD28跨膜(TM)域、Aiolos及CD3ζ ITAM域之「第二多肽」)進行編碼的第二聚核苷酸。將第二聚核苷酸選殖至慢病毒載體中。CAR 構建體在 T 細胞 中之表現 藉由T細胞檢測上述CAR構建體之表現。為分離T細胞，將周邊血液單核細胞(PBMC)與健康供體血液分離(例如，使用Ficoll Paque PlusTM 密度梯度離心(GE Healthcare, Piscataway, NJ)將PBMC與全血衍生之白血球層分離)。Pan T細胞負性地選自PBMC (例如，根據製造商的指令藉由使用Pan T分離套組II (Miltenyi Biotec, Cambridge, MA))。 將包含對第一多肽及第二多肽CAR進行編碼之構建體的質粒引入(例如，藉由電穿孔)至原代T細胞中，且接著在介質(例如，RPMI-10)中培養經電穿孔之T細胞隔夜。偵測到CAR之抗原結合域之表現，藉由對第一多肽進行編碼之構建體來確定T細胞之穩定轉染。舉例而言，T細胞在電穿孔後24小時處經捕獲且經染色以偵測第一多肽之抗原結合域(例如，對於抗-HER2偵測，用HER2人類IgG-Fc嵌合體蛋白染色，接著用與APC共軛之抗人類IgG-Fc抗體染色)。藉由流式細胞量測術分析經染色細胞。藉由對第二多肽進行編碼之構建體來確認T細胞之穩定轉染。舉例而言，在補充有泊利度胺或來那度胺之介質(例如，RPMI-10)中培養T細胞隔夜。T細胞在電穿孔後24小時處經捕獲且接著在藉由可結合第一多肽之抗原結合域(例如，對於抗-HER2偵測，HER2人類IgG-Fc嵌合體蛋白)之試劑免疫沈澱之後裂解。用可偵測且標記第二多肽之Aiolos或CD3ζ域的試劑(例如，抗人類Aiolos抗體或抗人類CD3ζ抗體)處理免疫沈澱。藉由ELISA分析經標記之免疫沈澱且偵測到第二多肽，從而藉由對第二多肽進行編碼之構建體確認T細胞之穩定轉染。使用泊利度胺或來那度胺來調節 CAR T 細胞在 癌症病患中之活性 在暴露於泊利度胺或來那度胺及腫瘤抗原後活化T細胞上之第一多肽及第二多肽CAR。泊利度胺及來那度胺在人體中具有良好耐受性。第一多肽及第二多肽 CAR 之官能性評估 對T細胞中之第一多肽及第二多肽執行官能性評估(例如，HER2-CAR之官能性評估；參看下文)。T細胞經第一多肽及第二多肽穩定轉染且在泊利度胺或來那度胺之缺失及存在下經固定化腫瘤抗原Fc嵌合體蛋白刺激。作為CD28共刺激之陽性對照，除包含CD3ζ ITAM胞內域及排除cereblon之外，產生與經指定為第一多肽之CAR構建體相同之另一構建體。作為陰性對照，執行第一多肽(亦即，僅第二多肽經轉染)、第二多肽(亦即，僅第一多肽經轉染)及第一多肽及第二多肽兩者(亦即，第一多肽或第二多肽皆未經轉染)之模擬轉染。 為評估T細胞之刺激，藉由流式細胞量測術及/或ELISA在刺激後48小時檢測T細胞激活標記CD69及CD71之表現。上調CD69及CD71表現指示T細胞之刺激。針對CD69表現及CD71表現測試經對第一多肽及第二多肽進行編碼之構建體及對陽性對照多肽及陰性對照多肽進行編碼之構建體轉染的T細胞。上調相對於在陰性對照細胞中之觀測到之CD69及CD71表現的經對第一多肽及第二多肽進行編碼之構建體轉染的T細胞中之CD69及CD71表現指示經對第一多肽及第二多肽進行編碼之構建體轉染的T細胞之刺激。乳癌之治療 個體具有已擴散至至少一個局部淋巴結之3期乳癌。在移除癌組織之手術後，藉由靜脈內注射歷時30分鐘向個體投與呈200 mL生理鹽水溶液之包含第一嵌合受體及第二嵌合受體(諸如上文所描述的第一多肽及第二多肽)的109 個與1010 之間個經修飾T淋巴球。第一嵌合受體包含與HER2結合之胞外抗原結合區、跨膜域、來自CD28之胞內共刺激域及cereblon域。第二嵌合受體包含跨膜域、cereblon相關蛋白(例如，Aiolos)及衍生自CD3ζ之信號轉染域。 在投與包含第一嵌合受體及第二嵌合受體之經修飾T淋巴球後之特定時段處(例如，投與該細胞群體後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，向個體投與泊利度胺或來那度胺。 替代地，首先向個體投與泊利度胺或來那度胺，接著在投與泊利度胺或來那度胺後之特定時段處(例如，投與泊利度胺或來那度胺後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，投與包含第一嵌合受體及第二嵌合受體之經修飾T淋巴球。 投與後30、60、90及180天，評定個體之剩餘乳房組織中之乳癌及至其他淋巴結之擴散。前列腺癌之治療 個體具有未擴散至局部或其他淋巴結(N0，M0)之T2期前列腺癌。組織學級別測定為G2。總體而言，該個體經測定患有II期前列腺癌。藉由靜脈內注射歷時30分鐘向個體投與呈200 mL生理鹽水溶液的包含第一嵌合受體及第二嵌合受體(諸如上文所描述之第一多肽及第二多肽)的109 個與1010 之間個之經修飾T淋巴球。第一嵌合受體包含與PSCA結合之胞外抗原結合區、跨膜域、胞內共刺激域CD28及cereblon域。第二嵌合受體包含跨膜域、cereblon相關蛋白(例如，Aiolos)及衍生自CD3ζ之信號轉染域。 在投與包含嵌合受體第一及第二嵌合受體之經修飾T淋巴球後之特定時段處(例如，投與該細胞群體後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，向個體投與泊利度胺或來那度胺。 替代地，首先向個體投與泊利度胺或來那度胺，接著在投與泊利度胺或來那度胺後之特定時段處(例如，投與泊利度胺或來那度胺後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，投與包含第一嵌合受體及第二嵌合受體之經修飾T淋巴球。 在投與後30、60及90天，再評定個體之前列腺癌階段及至淋巴結之擴散，且執行活檢前列腺組織之組織學分析。多發性骨髓瘤之治療 個體具有先前已用至少一個治療過程(之，例如，來那度胺或泊利度胺)治療之III期多發性骨髓瘤(藉由國際分期系統(International Staging System)或Durie-Salmon系統)的。藉由靜脈內注射歷時30分鐘向個體投與呈 200 mL生理鹽水溶液之包含第一嵌合受體及第二嵌合受體(諸如上文所描述之第一多肽及第二多肽)的介於108 個與1010 之間個經修飾T淋巴球。第一嵌合受體包含與BCMA結合之胞外抗原結合區、跨膜域、胞內共刺激域CD28及cereblon域。第二嵌合受體包含跨膜域、cereblon相關蛋白(例如，Aiolos)及衍生自CD3ζ之信號轉導域。 在投與包含第一嵌合受體及第二嵌合受體之經修飾T淋巴球後之特定時段處(例如，投與該細胞群體後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，向個體投與泊利度胺或來那度胺。 替代地，首先向個體投與泊利度胺或來那度胺，接著在投與泊利度胺或來那度胺後之特定時段處(例如，投與泊利度胺或來那度胺後之30分鐘、1小時、6小時、12小時、1天、2天、3天、4天、5天、6天或1週)，投與包含第一嵌合受體及第二嵌合受體之經修飾T淋巴球。 投與後之30、60及90天，再評定個體之多發性骨髓瘤階段。等效物 本發明之範疇不受本文所描述之特定實施例限制。實際上，本文提供之標的物的各種修改，除所述彼等修改之外，將由以上描述而變得對熟習此項技術者顯而易見。此類修改意欲處於所附申請專利範圍之範疇內。 本文列舉各種公開案、專利及專利申請案，其揭示內容以全文引用的方式併入。On-target but off-target tumor effects (which may produce toxicity) mediated by therapeutic immune cells expressing CARs can be regulated by such cells in both primary and co-stimulatory signals required for activation. performance is reduced or eliminated. As disclosed herein, this separation is accomplished through the use of a CAR comprising two artificial polypeptides, wherein: (i) the first polypeptide comprises cereblon (or a functional portion thereof) and the second polypeptide comprises a cereblon-related protein (or its functional moiety); (ii) partitioned on two polypeptides into the components of the CAR required for activation; and (iii) the CAR is activated in the presence of a cereblon-binding compound that binds cereblon and cereblon-related proteins. CAR-mediated on-target but off-target tumor effects can also be reduced or eliminated by the use of dimerized artificial cell death receptors that allow for the optional killing of cells expressing such receptors. As described herein, such dimerizable artificial cell death receptors comprise a first polypeptide (comprising an apoptosis-inducing domain and a dimerization domain, such as cereblon (or a functional portion thereof)) and a second polypeptide (comprising Apoptosis-inducing domains and complementary dimerization domains, such as cereblon-associated protein (or functional parts thereof)). Cells expressing such dimerizable artificial cell death receptors can be induced to undergo apoptosis by contacting them with a cereblon-binding compound capable of dimerizing a first polypeptide and a second polypeptide, and thereby activate Apoptosis-inducing domain. 4.1. Chimeric Antigen Receptors and Uses Thereof 4.1.1 Chimeric Antigen Receptor Constructs Provided herein are chimeric antigen receptors (CARs) comprising: (a) a first polypeptide comprising cereblon or a functional portion thereof and (b) a second polypeptide comprising a cereblon-associated protein or a functional portion thereof, wherein the first polypeptide or the second polypeptide or both polypeptides comprise the remaining components of the CAR, such as an antigen binding domain, a transmembrane domain , a cell signaling domain and/or a co-stimulatory domain. When the first polypeptide and the second polypeptide of the CAR are expressed together in an immune cell (e.g., in T lymphocytes or natural killer cells) in the presence of a cereblon-binding compound, the cereblon of the first polypeptide (or its functional portion) and the cereblon-associated protein (or functional portion thereof) of the second polypeptide bind to the cereblon-binding compound so that a heterodimer with CAR functionality is formed. Thus, the activity (e.g., in vivo activity) of the CARs described herein can be determined by making cells expressing the first and second polypeptides of the CAR (e.g., T lymphocytes engineered to express the CARs) Selective control is achieved by exposure to cereblon-binding compounds. As used herein, "transmembrane domain" includes: transmembrane domains, wherein proteins comprising transmembrane domains comprise both intracellular and extracellular domains; and membrane anchoring domains, wherein proteins comprising transmembrane domains comprise Intracellular domain but not extracellular domain. In a specific embodiment, provided herein is a CAR comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and cereblon or a functional portion thereof, wherein the cereblon (or a functional portion thereof) capable of binding to a cereblon-binding compound; and (b) a second polypeptide comprising a transmembrane domain, a cereblon-associated protein or a functional portion thereof, and a primary cell signaling domain, wherein the cereblon-associated protein (or a functional portion thereof) Capable of binding a cereblon-binding compound; wherein in the presence of the cereblon-binding compound, the first polypeptide and the second polypeptide form a heterodimer. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and cereblon or a functional part thereof in order from the N-terminus to the C-terminus; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, a cereblon-associated protein or a functional part thereof, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, cereblon or a functional part thereof, and a transmembrane domain in order from the N-terminus to the C-terminus; and (b) a second polypeptide comprising, in order from the N-terminus to the C-terminus, a cereblon-related protein or a functional part thereof, a transmembrane domain, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, provided herein is a CAR comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and a cereblon-related protein or a functional portion thereof, wherein the cereblon-related protein (or a functional portion thereof) capable of binding to a cereblon-binding compound; and (b) a second polypeptide comprising a transmembrane domain, cereblon, or a functional portion thereof, and a primary cell signaling domain, wherein the cereblon (or functional portion thereof ) is capable of binding a cereblon-binding compound; wherein in the presence of the cereblon-binding compound, the first polypeptide and the second polypeptide form a heterodimer. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In a specific embodiment, the cereblon-binding compound is polilidomide (4-amino-2-[(3RS)-(2,6-dioxahexahydropyridin-3-yl)-1H-isoindole -1,3(2H)-dione). In another specific embodiment, the cereblon-binding compound is thalidomide ((RS)-2-(2,6-dioxahexahydropyridin-3-yl)-1H-isoindole-1,3( 2H)-diketone). In another specific embodiment, the cereblon-binding compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piper pyridine-2,6-dione). In another specific embodiment, the cereblon-binding compound is 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-iso Indol-2-yl]-piperidine-2,6-dione. In another specific embodiment, the cereblon binding compound is 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl) Oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, and a cereblon-related protein or functionalities thereof in order from the N-terminus to the C-terminus and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, cereblon or a functional portion thereof, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In a specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising, in order from N-terminus to C-terminus, an antigen-binding domain, a cereblon-related protein or a functional part thereof, and a transmembrane and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, cereblon or a functional portion thereof, a transmembrane domain, and a primary T cell signaling domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain. In another specific embodiment, the first polypeptide and the second polypeptide comprise a co-stimulatory domain. In another specific embodiment, the first polypeptide comprises a co-stimulatory domain and the second polypeptide does not comprise a co-stimulatory domain. In another specific embodiment, the second polypeptide comprises a co-stimulatory domain and the first polypeptide does not comprise a co-stimulatory domain. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, cereblon or a functional part thereof in order from N-terminus to C-terminus, and a primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, a cereblon-associated protein or a functional portion thereof, and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising, in order from N-terminus to C-terminus, an antigen-binding domain, cereblon or a functional part thereof, a transmembrane domain, and A polypeptide comprising a primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a cereblon-associated protein or a functional portion thereof, a transmembrane domain and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising an antigen-binding domain, a transmembrane domain, a cereblon-related protein, or functionalities thereof in order from the N-terminus to the C-terminus part and primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, a transmembrane domain, cereblon or a functional portion thereof, and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, a CAR is provided herein, comprising: (a) a first polypeptide comprising, in order from the N-terminus to the C-terminus, an antigen-binding domain, a cereblon-related protein or a functional part thereof, a transmembrane domain and a polypeptide comprising a primary cell signaling domain; and (b) a second polypeptide comprising, in order from N-terminus to C-terminus, cereblon or a functional portion thereof, a transmembrane domain and a co-stimulatory domain. In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another embodiment, both the cereblon (or its functional part) and the cereblon-related protein (or its functional part) are capable of binding to a cereblon-binding compound, wherein the cereblon-binding compound is polilidomide, thalidomide , Lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl] -piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy )-1-oxoisoindolin-2-yl)piperidine-2,6-dione. Cereblon and Cereblon -related proteins CARs provided herein comprise polypeptides comprising cereblon or a functional portion thereof or a cereblon-related protein (eg, Aiolos or Ikaros) or a functional portion thereof. As used herein, the term "functional portion" of a cereblon or cereblon-related protein is defined as a portion of a cereblon or cereblon-related protein capable of binding a cereblon-binding compound. In some embodiments, the functional portion of the cereblon or cereblon-related protein comprises the entire polypeptide coding sequence of the cereblon or the cereblon-related protein. In other embodiments, the functional portion of cereblon or a cereblon-related protein comprises a truncation of the cereblon or the cereblon-related protein, respectively. Those skilled in the art will recognize the components of each protein that are required to maintain function and/or to ensure binding of each protein to the cereblon-binding compound. In other embodiments, the functional portion of cereblon or cereblon-related protein comprises a peptide sequence derived from the cereblon or the cereblon-related protein, respectively. Those skilled in the art will recognize the components of each protein that are required to maintain function and/or to ensure binding of each protein to the cereblon-binding compound. In some embodiments, a CAR provided herein comprises a polypeptide comprising cereblon or a functional portion thereof capable of binding a cereblon-binding compound. In some embodiments, a CAR provided herein comprises a polypeptide comprising a cereblon-associated protein (eg, Aiolos or Ikaros) or a functional portion thereof capable of binding a cereblon-binding compound. In some embodiments, a CAR provided herein comprises a polypeptide comprising an Aiolos or a functional portion thereof capable of binding a cereblon binding compound. In certain embodiments, the CAR provided herein comprises: (i) a first polypeptide comprising cereblon or a functional portion thereof capable of binding a cereblon-binding compound; and (ii) a second polypeptide comprising a compound capable of binding cereblon A cereblon-related protein (eg, Aiolos or Ikaros) or a functional portion thereof that binds the compound. Cereblon is also known as the protein "Mental Retardation Non-Syndromic Autosomal Recessive 2A", CRBN, MRT2, MRT2A, and AD-006. Exemplary nucleic acids encoding cereblon are provided, for example, under Genbank Gene ID: 51185. An exemplary cereblon amino acid sequence is provided, for example, under Uniprot ID: Q96SW2-1. Those skilled in the art will readily understand how to use recombinant engineering to make and use cereblon-containing polypeptides. As used herein, the term "cereblon" refers to a naturally occurring cereblon protein or portion thereof and includes at least 80%, 85%, 90%, 95%, 96%, 97%, Polypeptides that are 98% or 99% homologous or identical in sequence, wherein the sequence can bind a cereblon-related protein, eg, in the presence of a cereblon-binding compound described herein. As used herein, "cereblon-associated protein" refers to a protein (or portion thereof) that acts as a substrate for cereblon, eg, that can bind to and/or associate with cereblon, eg, in the presence of a cereblon-binding compound. See, eg, Gandhi et al., 2014, Br. J. Haematol. 164(6): 811-821. In a specific embodiment, the cereblon-associated protein used in the CAR described herein is Aiolos. Aiolos is also known as "IKAROS family zinc finger 3", "zinc finger protein, subfamily 1A, 3" and ZNFN1A3. Exemplary nucleic acids encoding Aiolos are provided under Genbank Gene ID: 22806. An exemplary Aiolos amino acid sequence is provided, eg, under Uniprot ID: Q9UKT9-1. Those skilled in the art will readily understand how to use recombinant engineering to make and use Aiolos-containing polypeptides. As used herein, the term "Aiolos" refers to a naturally occurring Aiolos protein or portion thereof and includes at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous or sequence identical polypeptides. In another specific embodiment, the cereblon-associated protein used in the CAR described herein is Ikaros. Ikaros is also known as "IKAROS family zinc finger 1", IKZF1, IK1, LYF1, LyF-1, CVID13, PPP1R92, PRO0758, ZNFN1A1 and HS.54452. Exemplary nucleic acids encoding Ikaros are provided, for example, under Genbank Gene ID: 10320. An exemplary Ikaros amino acid sequence is provided, for example, under Uniprot ID: Q03267-1. Those skilled in the art will readily understand how to use recombinant engineering to make and use Ikaros-containing polypeptides. As used herein, the term "Ikaros" refers to a naturally occurring Ikaros protein or portion thereof and comprises at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous or sequence identical polypeptides. Antigen Binding Domain The antigen binding domain of the CAR provided herein can be any polypeptide domain, motif or sequence that binds to an antigen. In certain embodiments, the antigen binding domain of a CAR described herein is the antigen binding portion of a receptor. In a specific embodiment, the antigen binding domain of the CAR described herein is a receptor for a ligand produced by a tumor cell. In certain embodiments, the antigen binding domain of a CAR described herein is the antigen binding portion of an antibody. In a specific embodiment, the antigen-binding domain of the CAR described herein is an antibody, an antibody chain, a single-chain antibody or an antigen-binding portion thereof, an Fc domain, a glycophosphatidylinositol anchor domain, or a scFv antibody fragment. In certain embodiments, the antigen binding domain of the CAR described herein is a peptide-based macromolecular antigen binding agent, such as a phage display protein. In certain embodiments, antigen binding by the antigen binding domain of a CAR described herein is restricted for antigen presentation associated with the major histocompatibility complex (MHC). In certain embodiments, the antigens bound by the antigen binding domains of the CARs described herein are MHC-independent. The antigen bound/recognized by the antigen binding domain of the CAR described herein can be any antigen of interest. In a specific embodiment, the antigen is an antigen expressed on the surface of a cell (eg, a tumor cell, such as a solid tumor cell or a hematological tumor cell). In a specific embodiment, the antigen bound/recognized by the antigen binding domain of the CAR described herein is an antigen on a tumor cell, for example, the antigen is TSA or TAA. Exemplary tumor cell antigens that can be recognized (i.e., bound by the antigen binding domain of the CAR) by the CARs described herein include, but are not limited to: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigens , α-fetoprotein, B cell maturation antigen (BCMA), BAFF, B-lymphoma cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4 , CD19, CD20, CD22, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200 , CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folic acid Receptor-a, Folate Receptor 1, G250/CAIX, GD2, GD3, Glycoprotein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, Human Scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, IL-6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, κ light chain, L1-CAM, λ light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylneuramine sugar acid, NKG2D ligand, NPC-1C, PDGF-R a, PDL192, phosphatidylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105 , SDC1, SLAMF7, sp17, TAG72, Tenascin C, TGF β2, TGF-I3, TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and Vimentin. In another specific embodiment, the antigen bound/recognized by the antigen binding domain of the CAR described herein is an antigen expressed on or associated with the following tumor cells: lymphoma/leukemia, lung cancer , breast cancer, prostate cancer, adrenocortical carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, melanoma (eg, malignant melanoma), skin carcinoma, colorectal carcinoma, desmoid tumor, desmoplasia Cell tumors, endocrine tumors, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, solid germ cell tumors, hepatoblastoma, neuroblastoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Holmes tumor, glioblastoma, myxoma, fibroma, lipoma, or similar tumors. In another specific embodiment, the antigen bound/recognized by the antigen binding domain of the CAR described herein is an antigen expressed on or associated with the following tumor cells: chronic lymphocytic leukemia ( small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, nodal Outer marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, vascular Internal large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma, T-lymphocyte prolymphocytic leukemia, T-lymphocyte large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-lymphoid leukemia Globe leukemia/lymphoma, extranodal NK/T lymphocytic lymphoma, nasal type, enteropathic T lymphocytic lymphoma, hepatosplenic T lymphocytic lymphoma, blastic NK cell lymphoma, mycosis fungoides, plug Zale syndrome, primary cutaneous pleomorphic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T lymphocytic lymphoma, peripheral T lymphocytic lymphoma (unspecified), pleomorphic large cell lymphoma , Hodgkin's lymphoma, or non-Hodgkin's lymphoma. In another specific embodiment, the antigen bound/recognized by the antigen binding domain of the CAR described herein is a non-tumor-associated antigen or a non-tumor-specific antigen. In certain embodiments, the antigen is related to the appearance of the tumor, eg, the tumor environment. For example, a tumor can induce an inflammatory state in the tissue surrounding the tumor and can release angiogenic growth factors, interleukins and/or cytokines that promote angiogenesis into the tumor and at its periphery. Thus, in certain embodiments, the antigen is a growth factor, interleukin, or interleukin (eg, a growth factor, interleukin, or interleukin associated with angiogenesis or angiogenesis). Such growth factors, cytokines, and interleukins may include, but are not limited to, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF) and interleukin-8 (IL-8). In another specific embodiment, the antigen bound/recognized by the antigen binding domain of the CAR described herein is a damage-associated molecular pattern molecule (DAMP; also known as as an alarm element). Exemplary DAMPs that can bind to the antigen binding domain of the CAR described herein include, but are not limited to, heat shock proteins, chromosome-associated protein high mobility group box 1 (HMGB1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), DNA, adenosine triphosphate, uric acid, and heparan sulfate. Transmembrane Domains The transmembrane domains of the CARs described herein may comprise any molecule known in the art that acts as a transmembrane domain, such as functions in the context of CARs known to those skilled in the art. The transmembrane domain of the CAR described herein can be obtained or derived from the transmembrane domain of any transmembrane protein, and can include all or a portion of this transmembrane domain. In a specific embodiment, the transmembrane domain of the first polypeptide and/or the second polypeptide of the CAR described herein is obtained or derived from a T cell receptor, e.g., the first polypeptide of the CAR described herein And/or the transmembrane domain of the second polypeptide is obtained or derived from the alpha chain of the T cell receptor, the beta chain of the T cell receptor, the zeta chain of the T cell receptor. In specific embodiments, the transmembrane domain of the first polypeptide and/or the second polypeptide of the CAR described herein is obtained or derived from CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154, interleukin receptor, interleukin receptor or growth factor receptor. Signaling domains The primary cell signaling domains of the CARs described herein may comprise any molecule known in the art that acts as a cell signaling domain, such as functions in the context of CARs known to those skilled in the art. In a specific embodiment, the cell signaling domain of the CAR described herein comprises a primary T cell signaling domain. In a specific embodiment, the primary cell signaling domain of the CAR described herein is or comprises ZAP-70 or a signaling variant thereof. In another specific embodiment, the primary cell signaling domain of the CAR described herein is or comprises an ITAM. In a specific embodiment, the ITAM is the ITAM of FcRγ, FcRβ, CD3ζ, CD3γ, CD3δ, CD3ε, CD5, CD22, 20 CD79a, CD79b, CD278 (ICOS), FcERI, CD66d, DAP10 or DAP12. Costimulatory Domains In certain embodiments, the first polypeptide and/or the second polypeptide of the CAR described herein comprises a costimulatory domain. The co-stimulatory domain of the CARs described herein may comprise any molecule known in the art that acts as a co-stimulatory domain, such as functions in the context of CARs known to those skilled in the art. In a specific embodiment, the costimulatory domain of the first polypeptide and/or the second polypeptide of the CAR described herein is obtained or derived from a costimulatory CD27 polypeptide sequence, a costimulatory CD28 polypeptide sequence, a costimulatory OX40 (CD134 ) polypeptide sequence, costimulatory 4-1BB (CD137) polypeptide sequence or costimulator-inducible T cell costimulator (ICOS) polypeptide sequence. In another specific embodiment, the co-stimulatory domain of the first polypeptide and/or the second polypeptide of the CAR described herein is or comprises the following: CD28, 4-1BB (CD137), OX40, activated NK cell receptor BTLA, Toll ligand receptor, CD2, CD7, CD27, CD30, CD40, CDS, ICAM-L LFA-1 (CD11a/CD18), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, DAP10, DAP12, Ligands of CD83, MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, interleukin receptors, integrins or signaling lymphocyte activation molecules. Other Modifications In certain embodiments, the first polypeptide and/or the second polypeptide of the CAR described herein further comprise a dimerization domain that is responsive to a modulator (ie, an agent other than a cereblon binding compound). In certain embodiments, the first polypeptide and/or the second polypeptide of the CAR described herein further comprises a T cell survival motif. A T cell survival motif can be any polypeptide sequence or motif that contributes to the survival of T lymphocytes after stimulation by an antigen. In certain embodiments, the T cell survival motif is or is derived from the following: CD3, CD28, intracellular signaling domain of the IL-7 receptor (IL-7R), intracellular signaling of the IL-12 receptor domain, the intracellular signaling domain of the IL-15 receptor, the intracellular signaling domain of the IL-21 receptor, or the intracellular signaling domain of the transforming growth factor ß (TGFß) receptor. 4.1.2. CAR Polypeptide Modification In certain embodiments, the first polypeptide and/or the second polypeptide of the CAR provided herein are modified by, for example, acylation, amidation, glycosylation, methylation, phosphorylation Modified by sulfation, sulfation, sumylation and/or ubiquitination (or other protein modification). In certain embodiments, the first polypeptide and/or the second polypeptide of the CAR provided herein are labeled with a label capable of providing a detectable signal, such as a radioisotope or a fluorescent compound. In certain embodiments, one or more side chains of the first polypeptide and/or the second polypeptide of the CAR provided herein are derivatized, for example, the cleavage and amino terminal residues are derivatized with succinic acid or Derivatization with other carboxylic acid anhydrides, or with, for example, imide esters (such as methyl picolimidate), pyridoxal phosphate, pyridoxal, chloroborohydride, trinitrobenzenesulfonic acid, O-methyl Derivatization of isourea, 2,4-pentanedione and reaction catalyzed by glyoxylate transaminase. In certain embodiments, the side carboxyl group, asparaginyl group or glutamyl group can be synthesized by reacting with carbodiimide (R—N=C=NR’) (such as 1-cyclohexyl-3- (2-morpholinyl-(4-ethyl) carbodiimide or 1-ethyl-3-(4-azonium-4,4-dimethylpentyl) carbodiimide) reacts selectively 4.1.3. Nucleic acids Provided herein are nucleic acids encoding the CARs described herein, that is, nucleic acids encoding the first polypeptide of the CAR described herein and the second polypeptide of the CAR described herein. Nucleic acid encoding the polypeptide. In certain embodiments, the first polypeptide of the CAR described herein is encoded by a first nucleic acid (polynucleotide) and the second polypeptide of the CAR described herein is encoded by a second nucleic acid (polynucleotide) encoding. In a specific embodiment, provided herein are nucleic acids (polynucleotides) encoding both the first polypeptide and the second polypeptide of the CAR described herein. Suitable for use in the production of The nucleic acids of the described CARs include DNA, RNA, and nucleic acid analogs. Nucleic acid analogs can be modified at base moieties, sugar moieties, or phosphate backbones, and can include deoxyuridine instead of deoxythymidine, 5-methyl- 2'-deoxycytidine or 5-bromo-2'-deoxycytidine in place of deoxycytidine.Modification of the sugar moiety may include modification of the 2'hydroxyl of ribose to form a 2'-O-methyl sugar or 2'-O - Allyl sugar. The deoxynucleoside phosphate backbone can be modified to produce a morpholino nucleic acid, wherein each base moiety is attached to a six-membered morpholino ring, or a peptide nucleic acid, wherein the deoxyphosphate backbone is passed through a pseudopeptide backbone Substitution and retention of four bases. See, eg, Summerton and Weller (1997) Antisense Nucleic Acid Drug Dev. 7:187-195; and Hyrup et al. (1996) Bioorgan. Med. Chain. 4:5-23. In addition, deoxy The phosphate backbone can be replaced by, for example, a phosphorothioate or phosphorodithioate backbone, a phosphoramidite, or an alkyl phosphotriester backbone. In certain embodiments, a CAR polypeptide-encoding nucleic acid described herein is comprised in In a nucleic acid vector. For example, cells of interest (for example, T lymphocytes) can use a nucleic acid (polynucleotide) containing the nucleic acid (polynucleotide) encoding the first polypeptide and/or the second polypeptide of the CAR described herein. Transformation of synthetic vectors, lentiviral or retroviral vectors, autonomously replicating plasmids, viruses (e.g., retroviruses, lentiviruses, adenoviruses, or herpesviruses) or the like. In a specific embodiment, comprising the The carrier of the first polypeptide and/or the second polypeptide of CAR is a retrovirus vector.In another specific embodiment, the carrier comprising the first polypeptide and/or the second polypeptide of CAR described herein is Lentiviral vectors. Lentiviral vectors suitable for transformation of cells (e.g., T lymphocytes) include, but are not limited to, U.S. Patent Nos. 5,994,136, 6,165,782, 6,428,953, 7,083,981, and Lentiviral vectors described in No. 7,250,299. Suitable HIV vectors for transformation of cells (eg, T lymphocytes) include, but are not limited to, those described in US Patent No. 5,665,577. In certain embodiments, a CAR polypeptide-encoding nucleic acid described herein is operably linked to a promoter. In a specific embodiment, the promoter is a T cell specific promoter, a natural killer (NK) cell specific promoter, an inducible promoter acting in T cells or NK cells, or a constitutive promoter. 4.1.4. Cells The CARs provided herein can be expressed in cells in which CAR expression is effective, that is, cells that have been engineered to contain a CAR-encoding nucleic acid provided herein such that after expression of the nucleic acid in the cell, the cell Express the CAR described herein. For example, the CARs described herein can be expressed in T lymphocytes or natural killer cells. Cells provided herein that express a CAR described herein are referred to as "CAR cells." In certain embodiments, provided herein are cells (e.g., T lymphocytes or natural killer cells) modified to express a CAR comprising: (i) a first polypeptide comprising cereblon capable of binding a cereblon-binding compound or a functional portion thereof; and (ii) a second polypeptide comprising a cereblon-associated protein (eg, Aiolos or Ikaros) capable of binding a cereblon-binding compound, or a functional portion thereof. In a particular embodiment, the first polypeptide further comprises an antigen binding domain and a transmembrane domain (and optionally a co-stimulatory domain). In a particular embodiment, the second polypeptide further comprises a transmembrane domain and a primary cell signaling domain (and optionally a co-stimulatory domain). In a specific embodiment, the CAR provided herein is expressed in T lymphocytes. T lymphocytes may be naive T lymphocytes or MHC restricted T lymphocytes. In certain embodiments, the T lymphocytes are tumor infiltrating lymphocytes (TILs). In certain embodiments, T lymphocytes are isolated from tumor biospecimens or expanded from T lymphocytes isolated from tumor biospecimens. In certain other embodiments, T lymphocytes have been isolated from peripheral blood, cord blood or lymph or expanded from T lymphocytes expanded from peripheral blood, cord blood or lymph. In a specific embodiment, pairs of cells (e.g., T lymphocytes) engineered to comprise/express a CAR described herein are to be administered as part of the therapeutic methods described herein. Lymphocytes) are autologous to the individual. In other embodiments, the cells (eg, T lymphocytes) engineered to comprise/express a CAR described herein are allogeneic to the individual to whom the cells (eg, T lymphocytes) are administered. Where allogeneic cells (e.g., T lymphocytes) are used to make CAR cells, it is preferred to select cells (e.g., T lymphocytes) that will reduce the likelihood of graft-versus-host disease (GVHD) in the individual . For example, in certain embodiments, virus-specific T-lymphocytes are selected for use in making CAR T-lymphocytes; it would be desirable for such lymphocytes to have the ability to bind to any receptor antigen and thus be transformed by any receptor antigen. Greatly reduced natural ability to be activated. In certain embodiments, receptor-mediated rejection of allogeneic cells (e.g., T lymphocytes) can be reduced by co-administering to the host one or more immunosuppressive agents that suppress Agents such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide or the like. In one embodiment, T lymphocytes are obtained from an individual, then optionally expanded, and then treated with a first vector encoding a first polypeptide of a CAR described herein and a second multiplicity of a CAR described herein. The peptide is transformed with a second vector encoding it, and then amplified if necessary. Double transformants can be selected using selectable markers unique to each of the vectors. In another embodiment, T lymphocytes are obtained from an individual, then optionally amplified, and then transformed with a vector encoding the first and second polypeptides of a CAR described herein, and then optionally amplified. increase. Selectable markers can be used to obtain cells containing the vector. In certain embodiments, in addition to the artificial co-stimulatory polypeptide (in embodiments using co-stimulatory polypeptides) or in addition to the first polypeptide and the second polypeptide (in CAR cells comprising antigen-binding signaling and co-stimulatory signaling In addition to the isolated polypeptide example), the T lymphocytes used to generate the CAR cells provided herein comprise native TCR proteins, such as TCR-α and TCR-β capable of forming native TCR complexes. In certain other embodiments, either or both of the primary genes encoding TCR-alpha and TCR-beta in T lymphocytes are modified to be non-functional, such as deletions of part or all or insertions mutation. In certain embodiments, the signaling domains of the CARs described herein can be used to promote the proliferation and expansion of CAR-containing/expressing cells (eg, T lymphocytes). For example, unmodified T lymphocytes and T lymphocytes comprising polypeptides comprising the CD3zeta signaling domain and the CD28 co-stimulatory domain can be expanded using antibodies to CD3 and CD28 (e.g., antibodies attached to beads). Added; see eg US Patent Nos. 5,948,893, 6,534,055, 6,352,694, 6,692,964, 6,887,466 and 6,905,681. Similarly, antibodies directed against signaling motifs can be used to stimulate the proliferation of cells (eg, T lymphocytes) comprising the CARs described herein. In certain embodiments, the CAR cells described herein comprise a "suicide gene" or "safety switch" capable of killing substantially all CAR cells when desired. For example, in certain embodiments, the CAR cells described herein comprise the HSV thymidine kinase gene (HSV-TK), which causes cell death upon contact with gancyclovir. In another embodiment, the CAR cell comprises an inducible caspase, e.g., an inducible caspase 9 (icaspase9), e.g., an inducible caspase 9 that allows dimerization with a specific small molecule drug, and a human FK506 binding protein fusion protein. See Straathof et al., Blood 105(11):4247-4254 (2005). In certain embodiments, the CAR cells provided herein further comprise an artificial cell death polypeptide comprising an apoptosis-inducing domain and a dimerization domain, wherein the artificial cell death polypeptide can be dimerized using a dimerizing agent , and wherein when the artificial cell death polypeptide is dimerized, the polypeptide produces an apoptosis-inducing signal in the cell. In a specific embodiment, the dimerizing agent is rapamycin or an analog of rapamycin (rapamycin analog). In another specific embodiment, the dimerizing agent is AP1903 (rimiducid). In another specific embodiment, the dimerizing agent is not a cereblon binding compound. In a specific embodiment, the dimerization domain is a FK binding domain or an analog thereof. In another specific embodiment, the dimerizing agent is an antibody that binds to the FK binding domain. 4.1.5. Methods of Use The CAR cells provided herein (e.g., T lymphocytes modified to contain/express the CARs described herein) can be used to treat a patient with a disease that needs to be targeted (e.g., killed) by the cells. or individuals of multiple types of cells. In a specific embodiment, provided herein are methods for killing target cells expressing an antigen bound by an antigen binding domain of a CAR described herein, wherein the methods comprise: (i) combining the target cells with a mixture comprising/ contacting a cell (e.g., a T cell or NK cell) expressing a CAR described herein; and (ii) contacting the CAR expressing cell with a cereblon-binding compound, wherein in the presence of the antigen and the cereblon-binding compound, the CAR expresses Cells become activated. In a specific embodiment, the target cell is a cancer cell, such as a blood cancer cell or a solid tumor cell. In another specific embodiment, the target cell expresses one or more of the following antigens or fragments thereof: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA) , BAFF, B-lymphoma cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor) , CD28, CD30 (TNFRSF8), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX , GD2, GD3, Glycoprotein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor, IGF -I, IgG1, IL-6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM , λ light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C, PDGF- R a, PDL192, phosphatidylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tenascin C, TGF β2, TGF-I3, TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In another specific embodiment, provided herein are methods of treating cancer, the methods comprising: (i) administering to an individual (e.g., a human individual) comprising/expressing a CAR described herein (e.g., comprising a CAR described herein) A population of CAR cells (e.g., T cells or NK cells) described herein encoding a nucleic acid or expressing a CAR described herein), wherein the CAR comprises an antigen binding domain specific for a cancer antigen (e.g., TSA or TAA); and (ii) administering to the individual a composition comprising a cereblon-binding compound. In a particular embodiment, the cell population is administered to the individual first, and then at a specified time period after administration of the cell population (e.g., 30 minutes, 1 hour, 6 hours, 12 hours, 1 hour after administration of the cell population). day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week), the composition comprising the cereblon-binding compound is administered. In a specific embodiment, the antigen bound by the CAR is: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA), BAFF, B-lymphoid Tumor cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor), CD28, CD30 (TNFRSF8 ), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX, GD2, GD3, sugar Protein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, IL -6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM, lambda light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C, PDGF-R a, PDL192, phospholipids Acylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tenascin C, TGF β2, TGF-I3 , TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In a specific embodiment, the cereblon-binding compound administered to an individual according to the methods of treating cancer described herein is polilidomide, thalidomide, lenalidomide, 3-[4-(4- Lin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4 -((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl ) piperidine-2,6-dione. A non-limiting list of cancers that may be treated according to the methods of treatment described herein include: lymphoma, leukemia, lung cancer, breast cancer, prostate cancer, adrenocortical carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, melanoma, skin cancer tumor, colorectal cancer, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, solid germ cell tumor, hepatoblastoma, neuroblastoma, non Rhabdomyosarcoma Soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioma, glioblastoma, myxoma, fibroma, and lipoma. Exemplary lymphomas and leukemias include (but are not limited to): chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulin Blood, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Diffuse large B-cell lymphoma, Mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, Burkitt's lymphoma, T lymphocytic prelymphocytic leukemia, T lymphocyte large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T lymphocytic leukemia/lymphoma, extranodal NK/T lymphocytic lymphoma, nasal type, enteropathic T lymphocytic lymphoma, liver and spleen T Lymphoblastic lymphoma, NK cell lymphoma, mycosis fungoides, Sézalay syndrome, primary cutaneous pleomorphic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T lymphocytic lymphoma , peripheral T lymphocytic lymphoma (not specified), pleomorphic large cell lymphoma, Hodgkin lymphoma, or non-Hodgkin lymphoma. The efficacy of the CAR cells described herein in treating a disease or disorder (e.g., in treating an individual with cancer) can be assessed by one or more criteria known to those of ordinary skill that are specific to a particular disease or disorder, To indicate the progression of a disease or condition. In general, one or more of these criteria move detectably (e.g., significantly) from a disease state value or range to a normal value or range or toward a normal value or range Administration of CAR cells (eg, CAR T lymphocytes) to an individual (eg, cancer) is effective. The CAR cells described herein can be formulated in any pharmaceutically acceptable solution, preferably a solution suitable for delivery of living cells, such as saline solution (such as Ringer's solution), gelatin, carbohydrates (such as , lactose, amylose, starch or the like), fatty acid esters, hydroxymethylcellulose, polyvinyl pyrolidine and the like. Such formulations are preferably sterilized prior to addition of CAR cells, and may be mixed with adjuvants such as lubricants, preservatives, stabilizers, emulsifiers, salts to affect osmotic pressure, buffering and coloring. Pharmaceutical carriers suitable for formulating the CAR cells described herein are known in the art and are described, for example, in WO 96/05309. In certain embodiments, the CAR cells (e.g., CAR T lymphocytes) described herein are formulated into a single dose, wherein the single dose comprises at least, at most, or about 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 or 1×10 11 CAR cells. In certain embodiments, CAR cells (e.g., CAR T lymphocytes) described herein are formulated for intravenous, intraarterial, parenteral, intramuscular, subcutaneous, intrathecal, or intraocular administration, or in Administration in a specific organ or tissue. Cereblon- binding compound As used herein, the term "cereblon-binding compound" refers to a compound capable of binding cereblon (or a functional portion thereof) and a cereblon-related protein (or a functional portion thereof) (e.g., Aiolos (or a functional portion thereof) ) or Ikaros (or a functional part thereof)) molecules (eg, small molecules or proteins/polypeptides (eg, antibodies)). In a particular embodiment, the cereblon binding compound is capable of binding both cereblon (or a functional portion thereof) and Aiolos (or a functional portion thereof), resulting in cereblon (or a functional portion thereof) and Aiolos (or a functional portion thereof) associations, such as the formation of heterodimers. In another specific embodiment, the cereblon binding compound is capable of binding both cereblon (or a functional portion thereof) and Ikaros (or a functional portion thereof), resulting in cereblon (or a functional portion thereof) and Ikaros (or a functional portion thereof) ), such as the formation of heterodimers. In a specific embodiment, the cereblon-binding compound used according to the methods described herein is polilidomide (4-amino-2-[(3RS)-(2,6-dioxahexahydropyridin-3-yl )-1H-isoindole-1,3(2H)-dione). In another specific embodiment, the cereblon-binding compound used according to the methods described herein is thalidomide ((RS)-2-(2,6-dioxahexahydropyridin-3-yl)-1H-iso indole-1,3(2H)-dione). In another specific embodiment, the cereblon-binding compound used in accordance with the methods described herein is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindo Indol-2-yl)piperidine-2,6-dione). In another specific embodiment, the cereblon binding compound used according to the methods described herein is 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1 ,3-Dihydro-isoindol-2-yl]-piperidine-2,6-dione. In another specific embodiment, the cereblon binding compound used according to the methods described herein is 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl) Methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. See, eg, US Patent Application Publication No. 2014/0162282, which is incorporated herein by reference in its entirety, for disclosures related to these compounds. A cereblon-binding compound or enantiomer or mixture of enantiomers or a pharmaceutically acceptable salt, solvent, hydrate, co-crystal, clathrate or polymorph thereof for use according to the methods described herein Formulations can be delivered as a single dose (such as, for example, a single bolus injection or oral lozenge or pill) or over time (such as, for example, continuous infusion over time or divided boluses over time). The cereblon-binding compounds used in accordance with the methods described herein can be formulated for intravenous, intraarterial, parenteral, intramuscular, subcutaneous, intrathecal, or intraocular administration, or for administration within a particular organ or tissue. 4.2. Artificial cell death polypeptides 4.2.1. Cell death polypeptide constructs Also provided herein are dimerizable artificial cell death receptors comprising a first polypeptide (comprising cereblon or a functional portion thereof) and a second polypeptide (comprising cereblon-associated protein or a functional portion thereof), when expressed in cells (eg, T lymphocytes or NK cells), these receptors can lead to cell death in the presence of cereblon-binding compounds. Cereblon, cereblon-related proteins, and cereblon-binding compounds are described in detail in Section 4.1 above. In a specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon (or a functional portion thereof) and functional portion); and (b) a second polypeptide comprising an apoptosis-inducing domain (or a functional portion thereof) and Aiolos (or a functional portion thereof), wherein the cereblon (or a functional portion thereof) and the Both Aiolos (or a functional portion thereof) are capable of binding a cereblon-binding compound, and wherein the first polypeptide and the second polypeptide dimerize in the presence of the cereblon-binding compound to generate an apoptosis-inducing signal. In a particular embodiment, the cereblon-binding compound is polilidomide, thalidomide, lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)- 1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4-((4-((4-(2,4- Difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon (or a functional portion thereof)); and (b) a second polypeptide comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon Related proteins (or functional parts thereof). In a specific embodiment, the second polypeptide comprises a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof) and a cereblon-associated protein (or a functional portion thereof) functional part)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising an extracellular domain (comprising cereblon (or Its functional part)), transmembrane domain and intracellular domain (comprising apoptosis-inducing domain (or its functional part)); and (b) the second polypeptide, it comprises cell apoptosis-inducing domain (or its functional part) Sexual parts) and cereblon-related proteins (or functional parts thereof). In another specific embodiment, the second polypeptide comprises a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof) and a cereblon-associated protein (or its functional part)). In another specific embodiment, the second polypeptide comprises a transmembrane protein comprising an extracellular domain (comprising cereblon-associated protein (or a functional portion thereof)), a transmembrane domain and an intracellular domain (comprising apoptosis death-inducing domain (or a functional portion thereof)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising an apoptosis-inducing domain (or its functional portion) and cereblon (or its functional portion); and (b) a second polypeptide comprising a transmembrane protein comprising a transmembrane domain and an intracellular domain (comprising an apoptosis-inducing domain ( or functional parts thereof) and cereblon-related proteins (or functional parts thereof)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. In another specific embodiment, provided herein is a dimerizable artificial cell death receptor comprising: (a) a first polypeptide comprising a transmembrane protein comprising an apoptosis-inducing domain (or a functional portion thereof) and cereblon (or a functional portion thereof); and (b) a second polypeptide comprising a transmembrane protein comprising an extracellular domain (comprising a cereblon-associated protein (or a functional portion thereof)) , a transmembrane domain, and an intracellular domain (comprising an apoptosis-inducing domain (or a functional portion thereof)). In a specific embodiment, the cereblon-associated protein is Aiolos or Ikaros. The apoptosis-inducing domain of a cell death polypeptide can be, for example, any protein or portion thereof that, upon dimerization, initiates an apoptosis-inducing signal. In certain embodiments, the apoptosis-inducing domain is any apoptotic protease that homodimerizes. In a particular embodiment, the apoptosis-inducing domain is or comprises a caspase, such as caspase 9, caspase 8, or caspase 3 (e.g., human caspase 9, human protease 8 or human caspase 3). The amino acid sequences of human caspases, including human caspase 9, human caspase 8, and human caspase 3, are well known in the art. For example, human caspase 3 is assigned NCBI Gene ID: 836; human caspase 8 is assigned NCBI Gene ID: 841; and human caspase 9 is assigned NCBI Gene ID: 842. In certain embodiments, the intracellular and extracellular domains that are or comprise the caspase domain are joined by a CD8α stem or a CD8β stem, at least part of which may serve as a transmembrane domain. 4.2.2. Nucleic Acids Provided herein are nucleic acids encoding the dimerizable artificial cell death receptors described herein, ie, encoding the first polypeptide of the dimerizable artificial cell death receptors described herein. A nucleic acid and a nucleic acid encoding a second polypeptide capable of dimerizing an artificial cell death receptor. In certain embodiments, the first polypeptide of the dimerizable artificial cell death receptor described herein is encoded by a first nucleic acid (polynucleotide) and the dimerizable artificial cell death receptor described herein The second polypeptide is encoded by a second nucleic acid (polynucleotide). In a specific embodiment, provided herein are nucleic acids (polynucleotides) encoding both the first and second polypeptides of the dimerizable artificial cell death receptors described herein. Nucleic acids suitable for use in preparing the artificial cell death receptors described herein include DNA, RNA, and nucleic acid analogs. Nucleic acid analogs can be modified at the base moiety, sugar moiety, or phosphate backbone, and can include deoxyuridine in place of deoxythymidine, 5-methyl-2'-deoxycytidine, or 5-bromo-2'-deoxy Cytidine was substituted for deoxycytidine. Modifications of the sugar moiety may include modification of the 2' hydroxyl of ribose to form 2'-O-methyl sugars or 2'-O-allyl sugars. The deoxynucleoside phosphate backbone can be modified to produce morpholino nucleic acids, where each base moiety is linked to a six-membered morpholino ring, or peptide nucleic acids, where the deoxynucleoside phosphate backbone is replaced by a pseudopeptide backbone and the four bases are retained base. See, eg, Summerton and Weller (1997) Antisense Nucleic Acid Drug Dev. 7:187-195; and Hyrup et al. (1996) Bioorgan. Med. Chain. 4:5-23. Additionally, the deoxyphosphate backbone may be replaced by, for example, a phosphorothioate or dithiophosphate backbone, a phosphoramidite, or an alkylphosphotriester backbone. In certain embodiments, an artificial cell death receptor-encoding nucleic acid described herein is contained within a nucleic acid vector. For example, cells of interest (e.g., T-lymphocytes) can use a nucleic acid (polynucleotide) comprising a nucleic acid (polynucleotide) encoding a first polypeptide and/or a second polypeptide of an artificial cell death receptor described herein. Transformation by synthetic vectors, lentiviral or retroviral vectors, autonomously replicating plasmids, viruses (eg, retroviruses, lentiviral adenoviruses, or herpesviruses), or the like. In a specific embodiment, the vector comprising the first polypeptide and/or the second polypeptide of the artificial cell death receptor described herein is a retroviral vector. In another specific embodiment, the vector comprising the first polypeptide and/or the second polypeptide of the artificial cell death receptor described herein is a lentiviral vector. Lentiviral vectors suitable for transformation of cells (e.g., T lymphocytes) include, but are not limited to, the lentiviral vectors described in U.S. Pat. . Suitable HIV vectors for transformation of cells (eg, T lymphocytes) include, but are not limited to, those described in US Patent No. 5,665,577. In certain embodiments, an artificial cell death receptor-encoding nucleic acid described herein is operably linked to a promoter. In a specific embodiment, the promoter is a T cell specific promoter, a natural killer (NK) cell specific promoter, an inducible promoter acting in T cells or NK cells, or a constitutive promoter. 4.2.3. Cells The artificial cell death receptors provided herein can be expressed in cells that express useful cells, that is, cells that have been engineered to contain an artificial cell death receptor encoding nucleic acid provided herein such that in Following expression of a nucleic acid in a cell, the cell expresses an artificial cell death receptor described herein. For example, the artificial cell death receptors described herein can be expressed on T lymphocytes or natural killer cells. Cells provided herein that express the artificial cell death receptors described herein are referred to as "cell death receptor cells." In a specific embodiment, the artificial cell death receptors provided herein are expressed in T lymphocytes. T lymphocytes may be naive T lymphocytes or MHC restricted T lymphocytes. In certain embodiments, the T lymphocytes are tumor infiltrating lymphocytes (TILs). In certain embodiments, T lymphocytes are isolated from tumor biospecimens or expanded from T lymphocytes isolated from tumor biospecimens. In certain other embodiments, T lymphocytes have been isolated from peripheral blood, cord blood or lymph or expanded from T lymphocytes expanded from peripheral blood, cord blood or lymph. In a specific embodiment, the cell death receptor cells described herein are autologous to the individual to whom they are administered (eg, T lymphocytes) as part of a method of treatment described herein. In other embodiments, the cell death recipient cells described herein are allogeneic to the individual to whom the cells (eg, T lymphocytes) are administered. Where allogeneic cells (e.g., T lymphocytes) are used to produce cells comprising/expressing artificial cell death receptors, it is preferred to select cells that will reduce the likelihood of graft-versus-host disease (GVHD) in the individual (eg, T lymphocytes). See Section 4.1. In one embodiment, T lymphocytes are obtained from an individual, then optionally expanded, and then treated with a first vector encoding a first polypeptide of an artificial cell death receptor described herein and an expression of an artificial cell death receptor described herein. The second polypeptide encoding the cell death receptor is transformed with a second vector and then optionally amplified. Double transformants can be selected using selectable markers unique to each of the vectors. In another embodiment, T lymphocytes are obtained from an individual, then optionally expanded, and then transformed with a vector encoding a first polypeptide and a second polypeptide of an artificial cell death receptor described herein, and Then amplify as needed. Selectable markers can be used to obtain cells containing the vector. In certain embodiments, in addition to an artificial co-stimulatory polypeptide (in embodiments where a co-stimulatory polypeptide is used) or in addition to the first polypeptide and the second polypeptide (in a cell comprising separate antigen-binding and co-stimulatory signaling In addition to the polypeptides in the Examples), the T lymphocytes used to generate the cell death receptor cells provided herein include native TCR proteins, such as TCR-alpha and TCR-beta, which are capable of forming native TCR complexes. In certain other embodiments, either or both of the primary genes encoding TCR-alpha and TCR-beta in T lymphocytes are modified to be non-functional, such as deletions of part or all or insertions mutation. A cell death receptor cell provided herein (e.g., comprising a dimerizable artificial cell death receptor encoding nucleic acid described herein or expressing a dimerizable artificial cell death receptor described herein (i.e., expressing a nucleic acid described herein) T cells or NK cells described as capable of dimerizing the first polypeptide and the second polypeptide of the artificial cell death receptor) can be in contact with cereblon-binding compounds (for example, in the presence of polilidomide, thalidomide, Amine, lenalidomide, 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl ]-piperidine-2,6-dione or 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione) are induced to undergo apoptosis. The cell death receptor cells provided herein can be further engineered to express a CAR, eg, a CAR comprising a tumor-specific antigen binding domain. For example, the CARs can be selected from first generation CARs (where only the signaling domain is CD3ζ), second generation CARs (which comprise a signaling domain from CD3ζ and a co-stimulatory domain from CD28) and third generation CARs (which comprises a signaling domain from CD3ζ and a co-stimulatory domain from CD28 and another protein such as 4-1BB). In a specific embodiment, the CAR of a cell death receptor cell provided herein comprises two or more extracellular antigen targeting domains. In another specific embodiment, the CAR of the cell death receptor cells provided herein comprises an ectodomain that binds to interleukin, which is a negative regulator of T cell activity, and an extracellular domain derived from a positive regulator of T cell activity. Intracellular domain of the interleukin receptor. In another specific embodiment, the compound (e.g., polilidomide, thalidomide, lenalidomide, 3-[4-(4-morpholin-4-ylmethyl -Benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4-((4-(( 4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)piperidine-2,6 -diketone) to induce apoptosis in cells containing artificial cell death receptors and CARs. 4.2.4. Methods of Use Cells provided herein (e.g., T lymphocytes) comprising an artificial cell death receptor provided herein and a CAR can be used in the treatment of one or more cells that need to be targeted by the cells described herein. An individual of a type of cell (eg, one or more types of cells to be killed) wherein the activity of the cell death receptor cell can be controlled by administering a cereblon-binding compound. In particular, cell death receptor cells can be used therapeutically due to their CAR component and can be killed if desired due to their cell death receptor component, wherein the killing is achieved by binding the cell death receptor cell to cereblon Compound contact to complete. In a specific embodiment, provided herein is a method for controlling the killing of target cells, wherein the method comprises: (i) causing the target cells to die with a cell comprising an artificial cell death receptor and a CAR provided herein Contacting a recipient cell (e.g., a T cell or NK cell) and, when permitted, (ii) contacting the cell death recipient cell with a cereblon-binding compound, wherein in the presence of the cereblon-binding compound, the cell death receptor is killed Cells, such as cell death receptor cells, undergo apoptosis. In a specific embodiment, the target cell is a cancer cell, such as a blood cancer cell or a solid tumor cell. In another specific embodiment, the target cell expresses one or more of the following antigens or fragments thereof: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA) , BAFF, B-lymphoma cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor) , CD28, CD30 (TNFRSF8), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX , GD2, GD3, Glycoprotein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor, IGF -I, IgG1, IL-6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM , λ light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C, PDGF- R a, PDL192, phosphatidylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tenascin C, TGF β2, TGF-I3, TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In another specific embodiment, provided herein is a method of treating cancer, wherein the method comprises: (i) administering to an individual diagnosed with cancer (e.g., a human individual) comprising an artificial cell death receptor as provided herein and a population of cell death receptor cells (e.g., T cells or NK cells) of a CAR, wherein the CAR comprises an antigen binding domain specific for a cancer antigen (e.g., TSA or TAA) and where permitted, (ii) causes the The cell death receptor cell is contacted with a cereblon-binding compound, wherein the cell death receptor cell undergoes apoptosis in the presence of the cereblon-binding compound. In a particular embodiment, the cell population is administered to the individual first, and then at a specified time period after administration of the cell population (e.g., 30 minutes, 1 hour, 6 hours, 12 hours, 1 hour after administration of the cell population). day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week), the composition comprising the cereblon-binding compound is administered. In another specific embodiment, the subject is administered the composition comprising the cereblon-binding compound first, and then at a specified time period after administration of the composition comprising the cereblon-binding compound (e.g., after the administration of the composition comprising the cereblon-binding compound 30 minutes, 1 hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week) after the composition is administered to the population of cells. In a specific embodiment, the antigen bound by the CAR is: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, alpha-fetoprotein, B cell maturation antigen (BCMA), BAFF, B-lymphoid Tumor cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor), CD28, CD30 (TNFRSF8 ), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA-4, DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor-a, folate receptor 1, G250/CAIX, GD2, GD3, sugar Protein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, IL -6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM, lambda light chain, Lewis Y, mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C, PDGF-R a, PDL192, phospholipids Acylserine, prostate-specific cancer antigen (PSCA), prostate cancer cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tenascin C, TGF β2, TGF-I3 , TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and/or vimentin. In a specific embodiment, the cereblon-binding compound administered to an individual according to the methods of treating cancer described herein is polilidomide, thalidomide, lenalidomide, 3-[4-(4- Lin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or 3-(4 -((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl ) piperidine-2,6-dione. A non-limiting list of cancers that may be treated according to the methods of treatment described herein include: lymphoma, leukemia, lung cancer, breast cancer, prostate cancer, adrenocortical carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, melanoma, skin cancer tumor, colorectal cancer, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, solid germ cell tumor, hepatoblastoma, neuroblastoma, non Rhabdomyosarcoma Soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioma, glioblastoma, myxoma, fibroma, and lipoma. Exemplary lymphomas and leukemias include (but are not limited to): chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulin Blood, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Diffuse large B-cell lymphoma, Mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, Burkitt's lymphoma, T lymphocytic prelymphocytic leukemia, T lymphocyte large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T lymphocytic leukemia/lymphoma, extranodal NK/T lymphocytic lymphoma, nasal type, enteropathic T lymphocytic lymphoma, liver and spleen T Lymphoblastic lymphoma, NK cell lymphoma, mycosis fungoides, Sézalay syndrome, primary cutaneous pleomorphic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T lymphocytic lymphoma , peripheral T lymphocytic lymphoma (not specified), pleomorphic large cell lymphoma, Hodgkin lymphoma, or non-Hodgkin lymphoma. EXAMPLE This example describes the generation and use of modified T lymphocytes comprising a chimeric antigen receptor (CAR), wherein the CAR comprises: a first polypeptide comprising an antigen binding domain specific for a tumor-specific antigen, a co-stimulatory domain and cereblon; and a second polypeptide comprising a cereblon-associated protein (eg, Aiolos) and a CD3ζ immunoreceptor tyrosine-based activation motif (ITAM) primary cell signaling domain. CAR Constructs The CAR depicted in Figure 1 was prepared using standard methods. Construction of cereblon (CRBN)-based CAR (i.e. scFv containing anti-tumor antigen antibody, CD28 transmembrane (TM ) domain, CD28 co-stimulatory domain, and the first polynucleotide encoding the "first polypeptide" of CRBN). The first polynucleotide is cloned into a lentiviral vector. A second polynucleotide encoding a second polypeptide, an Aiolos-based ITAM CAR (ie, a "second polypeptide" comprising the CD28 transmembrane (TM) domain, Aiolos, and CD3ζ ITAM domain) was constructed. The second polynucleotide is cloned into the lentiviral vector. Expression of CAR constructs in T cells The expression of the above-mentioned CAR constructs was detected by T cells. To isolate T cells, peripheral blood mononuclear cells (PBMC) are separated from healthy donor blood (e.g., PBMC are separated from whole blood-derived buffy coat using Ficoll Paque Plus ™ density gradient centrifugation (GE Healthcare, Piscataway, NJ)) . Pan T cells are negatively selected from PBMCs (eg, by using Pan T Isolation Kit II (Miltenyi Biotec, Cambridge, MA) according to the manufacturer's instructions). A plasmid comprising a construct encoding the first polypeptide and the second polypeptide CAR is introduced (e.g., by electroporation) into primary T cells, and then cultured in a medium (e.g., RPMI-10). Electroporate T cells overnight. The expression of the antigen-binding domain of the CAR is detected, and the stable transfection of T cells is confirmed by the construct encoding the first polypeptide. For example, T cells are captured 24 hours after electroporation and stained to detect the antigen binding domain of the first polypeptide (e.g., for anti-HER2 detection, stain with HER2 human IgG-Fc chimera protein, This was followed by staining with an anti-human IgG-Fc antibody conjugated to APC). Stained cells were analyzed by flow cytometry. Stable transfection of T cells was confirmed by constructs encoding the second polypeptide. For example, T cells are cultured overnight in medium (eg, RPMI-10) supplemented with polilidomide or lenalidomide. T cells are captured 24 hours after electroporation and then after immunoprecipitation by reagents that bind the antigen binding domain of the first polypeptide (e.g., for anti-HER2 detection, HER2 human IgG-Fc chimera protein) Crack. The immunoprecipitate is treated with a reagent that detects and labels the Aiolos or CD3ζ domain of the second polypeptide (eg, an anti-human Aiolos antibody or an anti-human CD3ζ antibody). Stable transfection of T cells by the construct encoding the second polypeptide was confirmed by analyzing the labeled immunoprecipitate by ELISA and detecting the second polypeptide. Using polilidomide or lenalidomide to modulate the activity of CAR T cells in cancer patients After exposure to polilidomide or lenalidomide and tumor antigens, the first polypeptide and the second polypeptide on T cells were activated. Peptide CAR. Pollidomide and lenalidomide are well tolerated in humans. Functional assessment of first and second polypeptide CARs A functional assessment is performed on the first and second polypeptides in T cells (eg, functional assessment of HER2-CAR; see below). T cells were stably transfected with the first polypeptide and the second polypeptide and stimulated with the immobilized tumor antigen Fc chimeric protein in the absence and presence of polilidomide or lenalidomide. As a positive control for CD28 co-stimulation, another construct identical to the CAR construct designated as the first polypeptide was generated except that the CD3ζ ITAM intracellular domain was included and cereblon was excluded. As negative controls, the first polypeptide (i.e., only the second polypeptide was transfected), the second polypeptide (i.e., only the first polypeptide was transfected), and the first polypeptide and the second polypeptide were performed. Mock transfection of both (ie, neither the first polypeptide nor the second polypeptide was transfected). To assess T cell stimulation, the expression of T cell activation markers CD69 and CD71 was detected by flow cytometry and/or ELISA 48 hours after stimulation. Upregulation of CD69 and CD71 expression is indicative of stimulation of T cells. T cells transfected with constructs encoding the first and second polypeptides and constructs encoding positive control polypeptides and negative control polypeptides were tested for CD69 expression and CD71 expression. Upregulation of CD69 and CD71 expression in T cells transfected with constructs encoding the first polypeptide and the second polypeptide relative to the expression of CD69 and CD71 observed in negative control cells indicates that the expression of the first polypeptide Stimulation of T cells transfected with the construct encoding the peptide and the second polypeptide. Treatment of Breast Cancer Individuals have stage 3 breast cancer that has spread to at least one regional lymph node. Following the surgery to remove the cancerous tissue, the subject is administered a drug comprising the first chimeric receptor and the second chimeric receptor (such as described above) as 200 mL of saline solution over 30 minutes to the subject by intravenous injection over 30 minutes. Between 10 9 and 10 10 modified T lymphocytes of the first polypeptide and the second polypeptide). The first chimeric receptor comprises an extracellular antigen-binding domain that binds to HER2, a transmembrane domain, an intracellular co-stimulatory domain from CD28, and a cereblon domain. The second chimeric receptor comprises a transmembrane domain, a cereblon-associated protein (eg, Aiolos), and a signaling domain derived from CD3ζ. At a specified time period after administration of the modified T lymphocytes comprising the first chimeric receptor and the second chimeric receptor (e.g., 30 minutes, 1 hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week), polilidomide or lenalidomide is administered to the subject. Alternatively, the individual is administered polilidomide or lenalidomide first, followed by administration of polilidomide or lenalidomide at a specified time period after administration of polilidomide or lenalidomide (e.g., administration of polilidomide or lenalidomide 30 minutes, 1 hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week) thereafter, administer the drug comprising the first chimeric receptor and the second chimeric receptor Modified T lymphocytes of the recipient. Thirty, 60, 90, and 180 days post-administration, subjects were assessed for breast cancer in the remaining breast tissue and spread to other lymph nodes. Treatment of Prostate Cancer Individuals have stage T2 prostate cancer that has not spread to regional or other lymph nodes (N0, M0). Histological grade was determined to be G2. Overall, the individual was determined to have stage II prostate cancer. A protein comprising a first chimeric receptor and a second chimeric receptor (such as the first and second polypeptides described above) is administered to the subject by intravenous injection over 30 minutes in 200 mL of saline solution. Between 10 9 and 10 10 modified T lymphocytes. The first chimeric receptor comprises an extracellular antigen-binding region that binds to PSCA, a transmembrane domain, an intracellular co-stimulatory domain CD28, and a cereblon domain. The second chimeric receptor comprises a transmembrane domain, a cereblon-associated protein (eg, Aiolos), and a signaling domain derived from CD3ζ. At a specified time period after administration of the modified T lymphocytes comprising the first and second chimeric receptors (e.g., 30 minutes, 1 hour, 6 hours, 12 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week), polilidomide or lenalidomide is administered to the subject. Alternatively, the individual is administered polilidomide or lenalidomide first, followed by administration of polilidomide or lenalidomide at a specified time period after administration of polilidomide or lenalidomide (e.g., administration of polilidomide or lenalidomide 30 minutes, 1 hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week) thereafter, administer the drug comprising the first chimeric receptor and the second chimeric receptor Modified T lymphocytes of the recipient. At 30, 60, and 90 days post-administration, subjects were reassessed for prostate cancer stage and spread to lymph nodes, and histological analysis of biopsied prostate tissue was performed. Treatment of Multiple Myeloma Individuals with stage III multiple myeloma (by the International Staging System or Durie-Salmon system). A protein comprising a first chimeric receptor and a second chimeric receptor (such as the first polypeptide and the second polypeptide described above) is administered to the individual by intravenous injection over 30 minutes in 200 mL of saline solution. Between 10 8 and 10 10 modified T lymphocytes. The first chimeric receptor comprises an extracellular antigen-binding region that binds to BCMA, a transmembrane domain, an intracellular co-stimulatory domain CD28, and a cereblon domain. The second chimeric receptor comprises a transmembrane domain, a cereblon-associated protein (eg, Aiolos), and a signaling domain derived from CD3ζ. At a specified time period after administration of the modified T lymphocytes comprising the first chimeric receptor and the second chimeric receptor (e.g., 30 minutes, 1 hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week), polilidomide or lenalidomide is administered to the individual. Alternatively, the individual is administered polilidomide or lenalidomide first, followed by administration of polilidomide or lenalidomide at a specified time period after administration of polilidomide or lenalidomide (e.g., administration of polilidomide or lenalidomide 30 minutes, 1 hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week) thereafter, administer the drug comprising the first chimeric receptor and the second chimeric receptor Modified T lymphocytes of the recipient. 30, 60, and 90 days after administration, the individual's multiple myeloma stage was reassessed. Equivalents The scope of the invention is not limited by the specific embodiments described herein. Indeed, various modifications of the subject matter provided herein, in addition to those described, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the appended claims. Various publications, patents, and patent applications are cited herein, the disclosures of which are incorporated by reference in their entirety.

圖1：使用cereblon結合化合物(例如，泊利度胺)以調節CAR T細胞活性。所展示為在T細胞(具有包含腫瘤抗原結合域、諸如CD28之共刺激域及cereblon的第一多肽，及包含諸如CD3ζ之ITAM及諸如Aiolos之cereblon相關蛋白的第二多肽)上之分裂CAR之示意圖，該T細胞在暴露於泊利度胺及腫瘤抗原後活化，其中泊利度胺藉由誘導分裂CAR之二聚化來調節CAR活性。CRBN：cereblon；POM：泊利度胺；Costim.域：共刺激域。Figure 1: Use of cereblon-binding compounds (eg, polilidomide) to modulate CAR T cell activity. Displayed as cleavage on T cells with a first polypeptide comprising a tumor antigen binding domain, a co-stimulatory domain such as CD28, and cereblon, and a second polypeptide comprising an ITAM such as CD3ζ and a cereblon-associated protein such as Aiolos Schematic representation of a CAR that activates T cells after exposure to polilidomide and tumor antigens, where polilidomide modulates CAR activity by inducing dimerization of a split CAR. CRBN: cereblon; POM: polilidomide; Costim. domain: co-stimulatory domain.

Claims (23)

一種嵌合抗原受體(CAR)，其包含：(a)第一多肽，其包含抗原結合域；跨膜域；cereblon；及原代細胞信號傳導域(primary cell signaling domain)，其中該cereblon能夠與cereblon結合化合物結合；其中該第一多肽不包含共刺激域；及(b)第二多肽，其包含跨膜域；Aiolos或Ikaros；及共刺激域，其中該Aiolos或Ikaros能夠結合該cereblon結合化合物；其中在該cereblon結合化合物之存在下，該第一多肽及該第二多肽形成異質二聚體。 A chimeric antigen receptor (CAR) comprising: (a) a first polypeptide comprising an antigen binding domain; a transmembrane domain; cereblon; and a primary cell signaling domain, wherein the cereblon capable of binding to a cereblon-binding compound; wherein the first polypeptide does not comprise a co-stimulatory domain; and (b) a second polypeptide comprising a transmembrane domain; Aiolos or Ikaros; and a co-stimulatory domain, wherein the Aiolos or Ikaros is capable of binding The cereblon-binding compound; wherein the first polypeptide and the second polypeptide form a heterodimer in the presence of the cereblon-binding compound. 如請求項1之CAR，其中該第一多肽按自N端至C端之順序包含：該抗原結合域、該跨膜域、該cereblon及該原代細胞信號傳導域；且該第二多肽按自N端至C端之順序包含：該跨膜域、該Aiolos或該Ikaros，及該共刺激域。 The CAR according to claim 1, wherein the first polypeptide comprises in order from the N-terminus to the C-terminus: the antigen-binding domain, the transmembrane domain, the cereblon and the primary cell signaling domain; and the second polypeptide The peptide comprises in order from N-terminal to C-terminal: the transmembrane domain, the Aiolos or the Ikaros, and the co-stimulatory domain. 如請求項1之CAR，其中該第一多肽按自N端至C端之順序包含：該抗原結合域、該cereblon、該跨膜域及該原代細胞信號傳導域；且該第二多肽按自N端至C端之順序包含：該Aiolos或該Ikaros、該跨膜域及該共刺激域。 The CAR according to claim 1, wherein the first polypeptide comprises in order from the N-terminus to the C-terminus: the antigen-binding domain, the cereblon, the transmembrane domain, and the primary cell signaling domain; and the second polypeptide The peptide comprises in order from N-terminal to C-terminal: the Aiolos or the Ikaros, the transmembrane domain and the co-stimulatory domain. 如請求項1之CAR，其中該原代細胞信號傳導域為CD3ζ。 The CAR according to claim 1, wherein the primary cell signaling domain is CD3ζ. 一種嵌合抗原受體(CAR)，其包含：(a)第一多肽，其包含抗原結合域；跨膜域；cereblon；及共刺激域，其中該cereblon能夠與cereblon結合化合物結合；其中該第一多肽不包含原代細胞信號傳導域；及(b)第二多肽，其包含跨膜域；Aiolos或Ikaros；及原代細胞信號傳導域，其中該Aiolos或Ikaros能夠結合該cereblon結合化合物；其中在該cereblon結合化合物之存在下，該第一多肽及該第二多肽形成異質二聚體。 A chimeric antigen receptor (CAR) comprising: (a) a first polypeptide comprising an antigen binding domain; a transmembrane domain; cereblon; and a co-stimulatory domain, wherein the cereblon is capable of binding to a cereblon-binding compound; wherein the The first polypeptide does not comprise a primary cell signaling domain; and (b) a second polypeptide comprising a transmembrane domain; Aiolos or Ikaros; and a primary cell signaling domain, wherein the Aiolos or Ikaros is capable of binding the cereblon binding A compound; wherein in the presence of the cereblon-binding compound, the first polypeptide and the second polypeptide form a heterodimer. 如請求項5之CAR，其中該第一多肽按自N端至C端之順序包含：該抗原結合域、該跨膜域、該cereblon及該共刺激域；且該第二多肽按自N端至C端之順序包含：該跨膜域、該Aiolos或該Ikaros，及該原代細胞信號傳導域。 The CAR of claim 5, wherein the first polypeptide comprises in order from N-terminus to C-terminus: the antigen-binding domain, the transmembrane domain, the cereblon, and the co-stimulatory domain; and the second polypeptide is in order from The sequence from N-terminal to C-terminal comprises: the transmembrane domain, the Aiolos or the Ikaros, and the primary cell signaling domain. 如請求項5之CAR，其中該第一多肽按自N端至C端之順序包含：該抗原結合域、該cereblon、該跨膜域及該共刺激域；且該第二多肽按自N端至C端之順序包含：該Aiolos或該Ikaros、該跨膜域及該原代細胞信號傳導域。 The CAR of claim 5, wherein the first polypeptide comprises in order from the N-terminus to the C-terminus: the antigen-binding domain, the cereblon, the transmembrane domain, and the co-stimulatory domain; and the second polypeptide is from the The sequence from N-terminal to C-terminal comprises: the Aiolos or the Ikaros, the transmembrane domain and the primary cell signaling domain. 如請求項5之CAR，其中該原代細胞信號傳導域為CD3ζ。 The CAR according to claim 5, wherein the primary cell signaling domain is CD3ζ. 如請求項1至8中任一項之CAR，其中該原代細胞信號傳導域為基於免疫受體酪胺酸的活化基元(ITAM)或包含該基於免疫受體酪胺酸的活化 基元。 The CAR according to any one of claims 1 to 8, wherein the primary cell signaling domain is an immunoreceptor tyrosine-based activation motif (ITAM) or comprises the immunoreceptor tyrosine-based activation primitive. 如請求項9之CAR，其中該ITAM為來自以下中之一或多者的信號傳導域：FcRγ、FcRβ、CD3ζ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD20、CD79a、CD79b、CD278(ICOS)、FcERI、CD66d、DAP10及DAP12。 The CAR of claim 9, wherein the ITAM is a signaling domain from one or more of the following: FcRγ, FcRβ, CD3ζ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD20, CD79a, CD79b, CD278 (ICOS) , FcERI, CD66d, DAP10 and DAP12. 如請求項1至8中任一項之CAR，其中該共刺激域包含以下中之官能性信號傳導域之一或多者：CD28、4-1BB(CD137)、OX40、活化NK細胞受體、BTLA、Toll配位體受體、CD2、CD7、CD27、CD30、CD40、CDS、ICAM-L LFA-1(CD11a/CD18)、B7-H3、CDS、ICAM-1、ICOS(CD278)、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、ITGB7、NKG2D、NKG2C、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、DAP10、DAP12、CD83之配位體、MHC I類分子、TNF受體蛋白、免疫 球蛋白類蛋白、細胞介素受體、整合素及信號傳導淋巴球性活化分子。 The CAR according to any one of claims 1 to 8, wherein the co-stimulatory domain comprises one or more of the following functional signaling domains: CD28, 4-1BB (CD137), OX40, activated NK cell receptor, BTLA, Toll ligand receptor, CD2, CD7, CD27, CD30, CD40, CDS, ICAM-L LFA-1(CD11a/CD18), B7-H3, CDS, ICAM-1, ICOS(CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1( CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSGL1, CD100(SEMA4D), CD69, SLAMF6(NTB-A, Ly108), SLAM Ligands of (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, DAP10, DAP12, CD83, MHC class I molecules , TNF receptor protein, immune Globulin-like proteins, interleukin receptors, integrins, and signaling lymphocyte activation molecules. 如請求項4之CAR，其中該共刺激域包含CD28或4-1BB(CD137)之官能性信號傳導域。 The CAR according to claim 4, wherein the co-stimulatory domain comprises a functional signaling domain of CD28 or 4-1BB (CD137). 如請求項8之CAR，其中該共刺激域包含CD28或4-1BB(CD137)之官能性信號傳導域。 The CAR according to claim 8, wherein the co-stimulatory domain comprises a functional signaling domain of CD28 or 4-1BB (CD137). 如請求項1至8、12及13中任一項之CAR，其中該跨膜域為來自以下的跨膜域：T細胞受體之α鏈、該T細胞受體之β鏈、該T細胞受體之ζ鏈、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154。 The CAR according to any one of claims 1 to 8, 12 and 13, wherein the transmembrane domain is a transmembrane domain from the following: the α chain of the T cell receptor, the β chain of the T cell receptor, the T cell The zeta chain of the receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154. 如請求項1至8、12及13中任一項之CAR，其中該抗原結合域為用於該抗原之受體。 The CAR according to any one of claims 1 to 8, 12 and 13, wherein the antigen-binding domain is a receptor for the antigen. 如請求項1至8、12及13中任一項之CAR，其中該抗原結合域為結合該抗原之抗體或其結合片段。 The CAR according to any one of claims 1 to 8, 12 and 13, wherein the antigen-binding domain is an antibody or a binding fragment thereof that binds the antigen. 如請求項1至8、12及13中任一項之CAR，其中該抗原結合域為結合該抗原之單鏈Fv片段(scFv)。 The CAR according to any one of claims 1 to 8, 12 and 13, wherein the antigen-binding domain is a single-chain Fv fragment (scFv) that binds the antigen. 如請求項1至8、12及13中任一項之CAR，其中該抗原為腫瘤相關抗 原(TAA)或腫瘤特異性抗原(TSA)。 The CAR according to any one of claims 1 to 8, 12 and 13, wherein the antigen is a tumor-associated antibody original (TAA) or tumor-specific antigen (TSA). 如請求項18之CAR，其中該TAA或TSA為以下中之一或多者：4-1BB、5T4、8H9、B7-H6、腺癌抗原、α-胎蛋白、B細胞成熟抗原(BCMA)、BAFF、B淋巴瘤細胞、C242抗原、CA9、癌胚抗原、CA-125、碳酸酐酶9(CA-IX)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23(IgE受體)、CD28、CD30(TNFRSF8)、CD33、CD38、CD40、CD44v6、CD44v7/8、CD51、CD52、CD56、CD74、CD80、CD123、CD152、CD171、CD200、CD221、CE7、CEA、C-MET、CNT0888、CTLA-4、DRS、EpCAM、ErbB2、ErbB3/4、EGFR、EGFRvIII、EphA2、EGP2、EGP40、FAP、胚胎AchR、纖維結合蛋白額外域B、葉酸受體a、葉酸受體1、G250/CAIX、GD2、GD3、醣蛋白75、GPNMB、HER2/neu、HGF、HLA-AI MAGE A1、HLA-A2 NY-ES0-1、HMW-MAA、人類分散因子受體激酶、IGF-1受體、IGF-I、IgG1、IL-6、IL-13、IL-13受體a2、IL-11受體a、胰島素類生長因子I受體、整合素a5I31、整合素avI33、κ輕鏈、L1-CAM、λ輕鏈、路易斯Y(Lewis Y)、間皮素、MORAb-009、MS4A1、MUC1、MUC16、黏蛋白CanAg、NCAM、N-羥乙醯基神經胺糖酸、NKG2D配位體、NPC-1C、PDGF-R a、PDL192、磷脂醯絲胺酸、前列腺特異性癌抗原(PSCA)、前列腺癌瘤細胞、PSMA、PSC1、RANKL、RON、ROR1、SCH 900105、SDC1、SLAMF7、sp17、TAG72、肌腱蛋白C、TGF β2、TGF-I3、TL1A、TRAIL-R1、TRAIL-R2、腫瘤抗原CTAA16.88、VEGF-A、VEGF受體、VEGFR-1、VEGFR2、TEM1、TEM8及波形蛋白。 The CAR of claim 18, wherein the TAA or TSA is one or more of the following: 4-1BB, 5T4, 8H9, B7-H6, adenocarcinoma antigen, α-fetoprotein, B cell maturation antigen (BCMA), BAFF, B lymphoma cells, C242 antigen, CA9, carcinoembryonic antigen, CA-125, carbonic anhydrase 9 (CA-IX), CCR4, CD3, CD4, CD19, CD20, CD22, CD23 (IgE receptor), CD28 , CD30(TNFRSF8), CD33, CD38, CD40, CD44v6, CD44v7/8, CD51, CD52, CD56, CD74, CD80, CD123, CD152, CD171, CD200, CD221, CE7, CEA, C-MET, CNT0888, CTLA- 4. DRS, EpCAM, ErbB2, ErbB3/4, EGFR, EGFRvIII, EphA2, EGP2, EGP40, FAP, embryonic AchR, fibronectin extra domain B, folate receptor a, folate receptor 1, G250/CAIX, GD2, GD3, Glycoprotein 75, GPNMB, HER2/neu, HGF, HLA-AI MAGE A1, HLA-A2 NY-ES0-1, HMW-MAA, Human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, IL-6, IL-13, IL-13 receptor a2, IL-11 receptor a, insulin-like growth factor I receptor, integrin a5I31, integrin avI33, kappa light chain, L1-CAM, lambda light chain, Lewis Y (Lewis Y), mesothelin, MORAb-009, MS4A1, MUC1, MUC16, mucin CanAg, NCAM, N-glycolylceramide, NKG2D ligand, NPC-1C, PDGF -R a, PDL192, phosphatidylserine, prostate specific cancer antigen (PSCA), prostate cancer tumor cells, PSMA, PSC1, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, sp17, TAG72, tenascin C , TGF β2, TGF-I3, TL1A, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGF receptor, VEGFR-1, VEGFR2, TEM1, TEM8 and vimentin. 如請求項1至8、12及13中任一項之CAR，其中當該第一多肽及該第二多肽在T細胞或NK細胞內表現且異二聚時，該CAR傳輸原代活化信號及共刺激信號；其中該原代活化信號及共刺激信號能夠活化該T細胞或NK細胞。 The CAR according to any one of claims 1 to 8, 12 and 13, wherein when the first polypeptide and the second polypeptide are expressed in T cells or NK cells and are heterodimerized, the CAR transmits primary activation signal and co-stimulatory signal; wherein the primary activation signal and co-stimulatory signal are capable of activating the T cell or NK cell. 如請求項1至8、12及13中任一項中任一項之CAR，其中該cereblon結合化合物為沙立度胺(thalidomide)((RS)-2-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)、來那度胺(lenalidomide)(3-(4-胺基-1-側氧基-1,3-二氫-2H-異吲哚-2-基)哌啶-2,6-二酮)、泊利度胺(pomalidomide)(4-胺基-2-[(3RS)-(2,6-二氧六氫吡啶-3-基)-1H-異吲哚-1,3(2H)-二酮)、3-[4-(4-嗎啉-4-基甲基-苯甲氧基)-1-側氧基-1,3-二氫-異吲哚-2-基]-哌啶-2,6-二酮；或3-(4-((4-((4-(2,4-二氟苯基)哌嗪-1-基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。 The CAR of any one of claims 1 to 8, 12 and 13, wherein the cereblon-binding compound is thalidomide ((RS)-2-(2,6-dioxahexahydro Pyridin-3-yl)-1H-isoindole-1,3(2H)-dione), lenalidomide (3-(4-amino-1-oxo-1,3- Dihydro-2 H -isoindol-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-[(3 RS )-(2,6 -dioxahexahydropyridin-3-yl)-1 H -isoindole-1,3(2 H )-dione), 3-[4-(4-morpholin-4-ylmethyl-benzyl Oxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione; or 3-(4-((4-((4- (2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)piperidine-2,6-di ketone. 一種聚核苷酸，其包含核酸序列，該核酸序列編碼包含如請求項1至21中任一項之CAR之該第一多肽及該第二多肽中的一者或兩者。 A polynucleotide comprising a nucleic acid sequence encoding one or both of the first polypeptide and the second polypeptide comprising the CAR according to any one of claims 1 to 21. 一種細胞，其包含如請求項22之聚核苷酸。 A cell comprising the polynucleotide according to claim 22.
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